Carl W. Cotman, PhD - US grants

This project is a multi-disciplinary approach with the goal of identifying the neurobiological basis of behavior changes in the aged. Dr. J. McGaugh and his group are studying the relationship between stress, pain threshold and transmitter systems in the aged. Their recent studies have identified age related changes in opiate receptor activity in various brain areas which appear to correlate with observed behavioral changes. Dr. Marshall and co-workers have continued to investigate sensorimotor disturbances in the aging rodent; most recently examining the pharmacological characteristics of central dopamine systems. Dr. Lynch and co-workers are studying the neurochemical and physiological correlates of long term potentiation. Dr. Cotman and co-workers are continuing their studies on lesion induced synaptic growth in aged brain. It now seems established that new connections for slower and there are fewer following brain injury in aged. Dr. Moldave and co-workers have shown that beta endorphin and enkephalins can inhibit protein synthesis in vitro. Their studies continue to analyze the capacity of aged cells to synthesize proteins.

The brain possesses remarkable plastic capabilities which adapt its circuitry in the course of normal function and in response to injury. We will continue studies on synaptic plasticity and remodeling focusing on the hippocampus as a model system. Recently, we reported that brain transplants survive better if placed in an injury several days after it is sustained. This correlated with an increase in neurotrophic factors. In our initial studies we used peripheral cultured neurons as an assay system. Now we will extend these studies using centrally derived neurons and characterize the nature of the factors. We will also determine whether or not injury produced by ischemia causes an increase in neurotrophic factors. These results together with previous results from mechanical and cytotoxic lesions should allow us to determine whether the response of neurotrophic factors to injury is general to several types of injury. Results from in vitro cell culture will be used to optimize the survival and growth of transplants and to explore the possibility that even adult neurons can be transplanted. Many of our transplant studies will focus on replacing the entorhinal cortex. In transplant studies carried out in the previous grant period we studied septal, striatal and raphe transplants. We found that raphe transplants do not form synapses. In order to complete this series of studies we plan to study whether cholinergic transplants form synapses using a monoclonal antibody to choline acetyltransferase. There is extensive information on the consequences of removal of the entorhinal cortex and now we will study its capacity to restore the circuitry to normal. The inputs and outputs of the transplants will be studied and we will determine how the outputs interact with lesion induced sprouting. In this series of studies we will also analyze the distribution of acidic amino acid receptors after lesions and after transplants using a newly developed autoradiographic technique. Overall we plan to study the requirements of neural survival and growth in vivo and in vitro and using conditions for optimal transplantation of neurons, rigorously analyze the circuits formed and the junctions restored.

This award will establish an undergraduate research experience site in the Department of Psychobiology in Neural Plasticity and Brain Function. The eight-week summer program will begin with a one-week lecture/seminar series designed to introduce eight students to the field and to the research of the various faculty. This will be followed by an active research experience in faculty laboratories on a defined project tailored to the goals of students and their advisors. Throughout this period, students will continue to interact with faculty in both formal and informal meetings. At the end of the program, students will present their findings to other students in the department and to the faculty. This proposal is a direct outgrowth of a highly successful one-week undergraduate Summer Institute offered last year which, upon encouragement from students and faculty, will now be expanded into an eight-week program.

The goal of this study is to examine the mechanisms by which early experience is encoded into olfactory-limbic circuitries during development. The experiments start from the perspective of the basic properties of NMDA receptor complex and work toward the investigation of possible learning mechanisms. This approach was selected with the design that an understanding of the biochemistry of this receptor system during development will provide necessary baseline data to develop and test hypotheses about the role of this receptor complex in the encoding of experience into specific neural circuits. In the proposed experiments we will examine the developmental regulation of components of the NMDA receptor complex, its recognition site(s) its allosteric regulatory site, and its coupling to phoshoinositide metabolism. Parallel electrophysiological experiments will be pursued to test the hypothesis that NMDA receptors have a greater involvement in early development at times coincidence with the encoding of stimuli into developing circuitries. Initially we will focus on the hippocampus, since this structure contains a high density of NMDA receptors and is known to be a key processing center for learning and memory. In the later phases of the study we will extend our experimental system to include the olfactory bulbs as a model of peripheral sensory input to the hippocampus. The olfactory system was chosen because its connections are only three synapses from the hippocampus and NMDA receptors have been shown to participate in early olfactory learning. The combination of this experimental system and a multidisciplinary approach of biochemistry, autoradiography and electrophysiology will permit the processes of early learning to be carried out at a comprehensive level not previously possible.

The functional state of the aged and Alzheimer's disease (AD) brain is most likely a dynamic equilibrium between the consequences of neurodegenerative events and the plastic mechanisms that attempt to compensate. The core proposal concentrates on this theme and involves a detailed analysis of entorhinal hippocampal circuitry in relation to plastic and pathological events. In AD the netorhinal cortex and hippocampus are particularly susceptible to pathology but also capable of plasticity. In animal models there is now extensive data on the mechanism of neuronal degeneration, plastic responses to neuronal loss and on hippocampal function in relation to cognition. A multidisciplinary approach is proposed that is designed to stimulate new discoveries in the etiology and treatment of AD. Three new projects and five pilot projects are proposed by the principal investigator and junior investigators in this group. Junior investigator projects: 1. Cellular and molecular mechanisms of plaque formation (J. Geddes). 2. Regulation of glial transport processes in aging and AD (R. Bridges). 3. Calcium homeostasis in peripheral cells from aged and AD patients (C. Peterson). Pilot projects: 1. Regulation on nerve growth factor mRNA in neurons and glia (P. Isackson). 2. Detoxification mechanisms in the aged and AD olfactory bulb (M. Leon). 3. Computer simulation of normal and abnormal synaptic transmission in Ad (D. Perkel). 4. MR imaging of limbic-hippocampal circuitry in AD (O. Naldoglu). 5. Motor memory compared to verbal memory in AD (M. Kean). Several themes run though the proposal. For example projects will focus on the hippocampal limbic system as related to olfactory function and cognition involving olfactory stimuli. At a molecular level we have emphasized neurotrophic functions, calcium homeostasis, and trophic mechanisms that may counteract, or even paradoxically, contribute to AD pathology. In this way research collaborations and new discoveries will be stimulated. Members of this program will also train pre- and post-doctoral students in aging and AD research. They will also participate in a seminar series which will catalyze new interactions and attract new investigators into the project.

In this renewal application, we propose to pursue a multi-level cellular and molecular program aimed at identifying and analyzing the mechanisms underlying the normal aging process, particularly those that lead to age- related neurodegenerative diseases such as Alzheimer's disease (AD). We will focus on two mutually complimentary themes: 1) the analysis of brain proteases and protease inhibitors, their regulation and their functions in aging and AD; and 2) the study of neurotrophic factors in relationships to optimal aging and AD. Data obtained from this program project and other groups and labs in the past several years suggest these molecular systems play a critical role in regulating degenerating and growth and establishing the resultant balance. In the area of protease regulation, Dr. Dennis Cunningham and coworkers will explore the basic properties of a protease inhibitor, protease nexin-I (PN-1), in the normal and AD brain. They seek to understand the basis and the significance of the large PN-1 decrease they recently identified in AD. Dr. Bill van Nostrand will pursue his recent discovery that he protease inhibitor protease nexin-II (PN-2) is the secreted form of the amyloid beta-protein precursor containing the Kunitz inhibitory domain. Dr. Gary Lynch will examine the possible relationship between degenerative events and calpain activation with respect to aging. in the area of neurotrophic factor regulation, Dr Ralph Bradshaw will investigate the types of fibroblast growth factors present in brain and their respective capacities to serve as neurotrophic factors. Dr. Chris Gall and Dr. Paul lsackson will define the stimulation conditions regulating the activity-dependent increase of nerve growth factor (IGF) mRNA in young versus aged animals and study the mechanisms generating this increase. In parallel studies, Dr. Carl Cotman will focus on possible molecular cascades regulating neurotropic factors, using an in vivo and in vitro approach; he will also carry out immunocytochemical and in situ hybridization experiments on PN-1 and PN-2. A central theme of our proposal is the development of a better understanding of the normal aging process. Accordingly, we propose to develop a core facility to increase the acquisition of quality post mortem brain tissues from healthy individuals as well as expand the collection of AD tissues.

This award provides funds to the Department of Psychobiology at the University of California, Irvine to continue to sponsor a successful undergraduate research experience in Neural Plasticity and Brain Function. The program originated with a one-week undergraduate Summer Institute that was expanded with NSF funding. The eight-week summer program begins with a one-week lecture/seminar series designed to introduce the students to the field and to the research of the various faculty. This is followed by an active research experience in faculty laboratories on a defined project tailored to the goals of the student and their advisors. Throughout this period, students continue to interact with faculty in both formal and informal meetings. At the end of the program, students present their findings to other students in the Department and to the faculty.

This award provides funds to the Department of Psychology at the University of California, Irvine to continue to sponsor an undergraduate research experience in Neural Plasticity and Brain Function. The highly successful program originated with a one-week undergraduate Summer Institute that was expanded last year with NSF funding. The eight- week summer program begins with a one-week lecture/seminar series designed to introduce the students to the field and to the research of the various faculty. This is followed by an active research experience in faculty laboratories on a defined project tailored to the goals of students and their advisors. Throughout this period, students continue to interact with faculty in both formal and informal meetings. At the end of the program, students present their findings to other students in the Department and to the faculty.

The functional state of the aged and Alzheimer's disease (AD) brain is most likely a dynamic equilibrium between the consequences of neurodegenerative events and the plastic mechanisms that attempt to compensate. The core proposal concentrates on this theme and involves a detailed analysis of entorhinal hippocampal circuitry in relation to plastic and pathological events. In AD the netorhinal cortex and hippocampus are particularly susceptible to pathology but also capable of plasticity. In animal models there is now extensive data on the mechanism of neuronal degeneration, plastic responses to neuronal loss and on hippocampal function in relation to cognition. A multidisciplinary approach is proposed that is designed to stimulate new discoveries in the etiology and treatment of AD. Three new projects and five pilot projects are proposed by the principal investigator and junior investigators in this group. Junior investigator projects: 1. Cellular and molecular mechanisms of plaque formation (J. Geddes). 2. Regulation of glial transport processes in aging and AD (R. Bridges). 3. Calcium homeostasis in peripheral cells from aged and AD patients (C. Peterson). Pilot projects: 1. Regulation on nerve growth factor mRNA in neurons and glia (P. Isackson). 2. Detoxification mechanisms in the aged and AD olfactory bulb (M. Leon). 3. Computer simulation of normal and abnormal synaptic transmission in Ad (D. Perkel). 4. MR imaging of limbic-hippocampal circuitry in AD (O. Naldoglu). 5. Motor memory compared to verbal memory in AD (M. Kean). Several themes run though the proposal. For example projects will focus on the hippocampal limbic system as related to olfactory function and cognition involving olfactory stimuli. At a molecular level we have emphasized neurotrophic functions, calcium homeostasis, and trophic mechanisms that may counteract, or even paradoxically, contribute to AD pathology. In this way research collaborations and new discoveries will be stimulated. Members of this program will also train pre- and post-doctoral students in aging and AD research. They will also participate in a seminar series which will catalyze new interactions and attract new investigators into the project.

Over the past several years, we have examined the molecular and cellular mechanisms of axon sprouting and reactive synaptogenesis. It is postulated that reactive synaptogenesis is part of an ongoing plasticity mechanism which can rebuild brain circuitry after minor cell loss such as occurs in aging and some degenerative diseases. We have studied these processes in the rodent brain, particularly following entorhinal lesions, and in the human Alzheimer's disease (AD) brain where entorhinal neurons also degenerate. Indeed, we and others find that many of the changes identified in the rodent brain also occur in the AD brain. Unique to AD, however, is the formation of senile plaques. It appears that one of the events occurring in the AD brain is the diversion of neuritic growth into senile plaques and the initiation of a cycle of sprouting, degeneration, and regeneration. This appears to be an example of dysfunctional plasticity which may place stress on neurons, contribute to synaptic dysfunction, and foster plaque formation. We hypothesize that one of the key molecular factors that has a central role in dysfunctional plasticity is beta-amyloid (Abeta). Abeta may enter cascades and disrupt them. That is, Abeta may organize the normal sequence of events following injury and induce a sequence of pathological cellular and molecular cascades. After injury to the healthy hippocampus, microglia and astrocytes regulate a sequence of cellular and molecular events that participate in and coordinate the removal of degenerating debris and initiate axon sprouting. Many of the same reactions occur in AD, however, Abeta reorganizes the normal cellular and molecular events, makes them largely irreversible, and engages a molecular cycle of localized growth and degeneration. The morphological hallmark of this mechanism is the senile plaque. As the plaque develops from an initial Abeta deposit, glial cells become involved and neurites, both sprouting and degenerating, become associated with the plaque. A central focus of this research will be to examine the role of glial cells, select trophic factors, heparan sulfate, and Abeta in relationship to brain plasticity and plaque formation. Recent preliminary data suggest that Abeta may have a profound influence on astrocyte and microglia function. Specifically, we will examine the action of Abeta as an "activating" factor for astrocytes, define the structure/activity relationship of the interaction and the ability of Abeta to initiate production of other molecules which, in turn, may further plaque progression, e.g., production of FGF-2, Apolipoprotein E and even amyloid precursor protein (APP) itself. We will examine the nature of signal transduction processes drawing initially from clues derived from studies on neurons. Studies in vitro will be paralleled by analyses in vivo and in postmortem control and AD tissues. Specifically, by using double and triple labeling methods and immunohistochemistry, we will continue to define the stages and mechanisms of plaque formation. We will determine whether astrocytes precede or follow Abeta condensation as indicated by thioflavine staining. We will also define whether astrocytes precede neuritic involvement. The stage at which astrocytes begin to participate will be compared to that for microglia. Finally, we will continue to pursue collaborations with other investigators in this program. In particular, we will examine neuronal responses of Abeta on APP processing in collaboration with Drs. Van Nostrand and Glabe, thrombin/Abeta actions on neurons with Dr. Cunningham, and aspects of glial regulation with Drs, Gall and Cunningham.

The primary goal of the Tissue and Peptide Resources Core will be to provide well characterized tissue specimens and supporting data for the analysis of the neurobiology of aging and dementia. This will greatly facilitate work relating basic research to clinical issues and add to our understanding of basic mechanisms occurring during human brain aging. Our increased understanding of the changes that accompany aging and Alzheimer's disease (AD) necessitates that human tissues be precisely characterized with respect to the locus, extent, and nature of neuropathology present, clinical manifestations of dementia, premortem conditions, medications, and agonal state, as well as the anatomical areas examined and the post-mortem interval. The-core will obtain well- characterized AD cases with different degrees of disease severity, mixed dementias (AD and Vascular) and Vascular dementia cases. Further, the core has begun an initiative to obtain control and transitional cases where the neuropathological criteria for AD have not yet been met. Specimens will be characterized for the nature of pathology, genotype (for apolipoprotein E), and the relationships of cellular and molecular changes to clinical and brain imaging data. This will be facilitated through the use of a central relationaI database under the auspices of the Alzheimer's Disease Research Center (ADRC). Further, core staff will assist investigators in case selection and will work to coordinate research projects within the program. In addition, the core will synthesize and make available well-characterized peptides for individual investigator's use. This peptide component is presented w+thin this core since its budget is modest and it relates to overall resource distribution to investigators.

DESCRIPTION: This a resubmission of a proposal that previously received an acceptable score. It is a collaborative project between Dr. Cotman's neuroanatomy lab at UC Irvine, and Dr. Milgrim's neurobehavioral lab at the the University of Toronto. The current proposal additionally includes a large colony of dogs at the Inhilation Toxicology Research Institute in New Mexico, directed by Dr. Muggenburg.The investigators propose that the aged canine is an appropriate model for studying the earliest, and perhaps most critical stages of Alzheimer's Disease. There is extensive deposition of beta amyloid in the aged canine brain, but the canine does not appear to progress to the later stages of senile plaque formation, nor are neurofibrillary tangles present. To date there has been no examination of how neuropatholgical changes in the aged canine relate to changes in cognitive ability. In this proposal, dogs of varying ages will be tested on a battery of neuropsychological tests to determine which are most sensitive to early changes in learning and memory, and to determine whether procedural tasks, which are relatively spared in aged humans, are similarly spared in aged canines. The current proposal has added olfactory tasks to the battery, as well as assessment of sensory performance. Tasks will be refined at the University of Toronto, and dogs will be tested at either the University of Toronto or the ITRI. Following sacrifice, Dr. Cotman's lab will: 1) quantify the level of b-amyloid accumulation, including assessment of vascular changes (amyloid angiopathy), 2) address synapse number using synaptophysin immunoreactivity, and 3) examine cytoskeletal changes using antibodies to phosphorylated (SMI-31, SMI-34, SMI-310) and non-phosphorylated (SMI-32, SMI- 311) neurofilament epitopes, and different phosphorylation sites on the microtubual associated proteins tau (tau-1, PHF-1, AT8), MAP2 and MAP5. Tissue will also be examined for other neuropathologic changes such as neuritic dystrophy. The hippocampus, entorhinal cortex, superior frontal cortex and cerebellum will be the focus of these examinations; the first three due to their involvement in the cognitive tasks examined and their vulnerability in Alzheimer's Disease. The cerebellum will serve as a control, as this area is relatively unaffected by Alzheimer's, and is less directly linked with the cognitive tasks under examination. Behavioral changes will be correlated with neuropathological findings in hopes of better understanding which component of pathology occurs first and/or contributes the most to age-related cognitive decline.

DESCRIPTION(Adapted from applicant's abstract): Exercise has been associated with enhanced cognitive function as well as maintenance of cognitive health. The molecular mechanisms that may underlie this improved brain functioning, however, are only beginning to be identified. Brain-derived neurotrophic factor (BDNF) has been demonstrated to enhance the survival of cortical neurons, promote their recovery after damage, and participate in use-dependent plasticity mechanisms such as long-term potentiation and learning. Thus, BDNF regulation is critical to brain functions. We have demonstrated that exercise (voluntary running) can increase the expression of multiple BDNF transcript forms in rat brain. This effect is rapid (occurring within hours of exercise onset) and is sustained. This effect is regionally selective and is particularly prominent in the hippocampus, a brain region not normally associated with motor activity. A large literature suggests that such trophic factor responses are regulated by many other variables, including specific neurotransmitter and hormone interactions. Recently, a cAMP-response element (CRE) has been identified on the exon III BDNF promoter. The CRE is active in constructs, which suggests the hypothesis that CRE-binding protein (CREB) and the regulation of CREB activity may serve as a convergence point for the regulation of induction of the exon Ill-containing BDNF transcript (exon III-BDNF). Various neurotransmitters, activation of voltage sensitive calcium channels and the hormone estrogen may converge on the regulation of CREB activity and thereby on exon 111BDNF mRNA expression. Exon l-BDNF expression may be regulated by neurotransmitters, estrogen and corticosteroids. Specific studies will be directed toward exploring the role of the NMDA receptor, cholinergic and moluminergic "stems on BDNF expression, because initial evidence suggests that they can modulate BDNF -ion. F," cholinergic and monaminergic systems also appear to modulate cognitive function and behaviaral state. In addition to studies on mechanism, parallel studies will be conducted on the age-dependency, regional specificity, and means to enhance BDNF expression by combined behavioral and pharmacological interventions. Data from the proposed experiments will provide an initial characterization of how a simple, widely practiced activity-exercise-regulates expression of BDNF, a molecule increasingly recognized for its critical role in brain function.

A variety of neurodegenerative disorders (e.g., Alzheimer's disease (AD)) are characterized by somal and neuritic degeneration in select brain regions. The fundamental mechanisms underlying neurodegeneration in these diseases are not well understood but remain an area of intense interest. Historically, experimental elucidation of relevant mechanisms has logically focused upon the neuronal cell body. Equally important, but nonetheless largely ignored, are degenerative events occurring in neurites. Mechanistically, neither the relative vulnerability of neurites to degenerative stimuli nor the relevant pathways driving neurite degeneration are understood. Since the brain's neuronal cell bodies and distal neuritic processes are separated by long distances, these two cellular compartments by definition must be exposed and respond to different microenvironments. In the AD brain for example, microenvironments will vary in their ability to sustain neuronal viability, with specific regions being characterized by a variety of degenerative stimuli (e.g., beta-amyloid accumulation, excitotoxic and oxidative stress inflammation). In this application, we propose that neurites exposed to such local toxic microenvironments will exhibit focal degenerative responses. Accordingly, we propose to study pathways that contribute to local neurite degeneration. Specifically, we will test the hypothesis that mechanisms of apoptosis classically associated with death in the cell body compartment also may be operative locally in spatially separated neurite compartments. Initially, we will use primary neuronal cultures to define degenerative parameters induced by various stimuli (both apoptotic and necrotic) known to cause cell death. We then will utilize a modified-Campenot chamber to evaluate the defined degenerative parameters in neuron cultures in which only the neuritic compartment is exposed to the toxic environment. Using this approach, we will study neuritic and somal mechanisms of degeneration after selective insult. These studies will include an analysis of caspase dependence, upstream pathways, and the cytoskeletal and synaptic proteins targeted in neurites. Further, we use this paradigm to examine how neuritic degeneration is modulated by over-expression of factors known to inhibit apoptotic cell death (e.g.,Bcl-2, CrmA) or promote AD pathology and perhaps vulnerability to cell death (e.g., AD-associated mutations in APP and presenilins). The studies proposed in this application will provide new and basic biological findings potentially relevant to a wide array of normal and pathological events involving synaptic remodeling and neurite degeneration.

During the past five years a canine model of aging has been evaluated, with emphasis on categorization of cognitive decline and links with neuropathology. We have demonstrated that aged canines show a decline in memory and learning and a corresponding increase in brain pathology. We specifically propose that working memory, and learning that involves abstract rules and requires flexibility, are particularly sensitive to age. These age sensitive functions are likely to depend on cortical circuits that converge in the prefrontal cortex. We further hypothesize that age-related impairment is partially attributable to oxidative stress that begins in middle age and triggers a cascade of events resulting in both accumulation of neurotoxic substances, such as beta-amyloid (A beta) protein and possibly cell dysfunction or death. The present proposal seeks first to extend our evaluation of the canine model and establish the cognitive processes that are particularly sensitive to aging, using both cross sectional and longitudinal strategies. Second, we propose to analyze key endpoints in an oxidative stress cascade that may be part of a sequence of neuropathological events underlying age-related impairment. Third, as a test of theory, we will use an intervention study to modify oxidative stress levels in dogs. Thus, this proposal incorporates a new component, to test the cognitive and neurobiological effects of intervention with a diet rich in a broad spectrum of antioxidants. This component of the proposal incorporates both a short-term (cross-sectional) and a long-term (longitudinal study) of cognition and brain aging in the dog. Specifically, direct measures of protein, lipid and DNA/RNA oxidation will be examined in control and treated animals along with hypothesized downstream consequences of oxidation serving as indirect measures, e.g., increased A beta, increased DNA strand breaks, caspase levels/activation and altered synaptic density. Overall, this project should provide unique insight into the role of oxidative damage and subsequent molecular cascades on the progression of brain aging and cognitive decline.

DESCRIPTION (Adapted from the application): The calcium hypothesis of AD, advanced over 12 years ago postulates that sustained disturbances in intracellular calcium regulation are a primary cause of AD neurodegeneration. Consistent with this hypothesis, changes in intracellular calcium not only mediate neuronal cell death, but also increase production of beta amyloid, which accumulates in diffuse and neuritic plaques, a hallmark feature of AD. Although these and other findings suggest that perturbed calcium homeostasis lies upstream of the amyloid cascade, this issue is still widely debated. With the identification of genes causally linked to AD, namely, presenilin-l and -2 (PSI and PS2), it is now possible to dissect the molecular and cellular events responsible for these changes in cultured cells and transgenic animals. The preliminary data show that several different AD-linked mutations in both PS 1 and PS2 all potentiate the phosphoinositide intracellular calcium signaling pathway at the level of calcium release from the endoplasmic reticulum. The first aim will establish whether multiple presenilin mutations share the common feature of altering intracellular calcium signaling. The second aim will test several specific hypotheses about the mechanisms underlying presenilins effects on this pathway. The investigators also have preliminary data suggesting that the presenilins may affect other intracellular calcium signaling pathways, including capacitative calcium entry, disturbances which may be an early and reliable diagnostic marker of familial AD. The third aim of this study examines the potential involvement of the presenilins in this and other intracellular calcium signaling pathways. The proposed experiments will use advanced molecular and pharmacological methods in combination with high-resolution microscopy. Experiments will be conducted in a range of cell types, including Xenopus oocytes, cultured cell lines, and will also feature the use of primary neurons isolated from mutant PSI knock-in animals, which represent the most advanced reagent available for the study of presenilin mutations. Data generated from these experiments are expected to significantly increase the understanding of presenilin function and could uncover novel targets for the early diagnosis and/or therapeutic intervention of AD.

DESCRIPTION (Adapted from the application): This proposal aims to establish a new ADRC at UCI which will focus on the basic cellular and molecular mechanisms of brain aging and AD, and seek to identify mechanisms of early pathogenic change and relate these mechanisms to cognitive and behavioral functions. Building upon the existing UCI Institute for Brain Aging and Dementia and continuing commitments by UCI to further develop Alzheimer s Disease (AD) research, the new ADRC will offer an opportunity to link pioneering basic research into early cellular and molecular mechanisms of AD to clinical applications, and apply clinical insights to basic research. The new ADRC will bring several themes to AD research: first and foremost is a cutting edge basic science perspective, second, a dedicated commitment to link basic and clinical studies, and third, an infrastructure to unite the ADRC and pioneer new initiatives that exploit the latest technological advances in bioinformatics. The technological initiatives, coordinated through the Data Management and Biostatistics Subcore, are directed at fostering investigator-initiated research and bridging clinical and basic research. The ADRC Projects are directed at investigating mechanisms hypothesized to contribute to early changes in AD brain that lead or contribute to AD progression. Three focus on cellular and molecular mechanisms. While there is always some debate, many investigators recognize three candidate mechanisms associated with the pathogenesis of AD: 1) beta-amyloid accumulation, 2) Inflammatory responses, and 3) Abnormalities in calcium homeostasis. Each of the projects addresses one of these candidate mechanisms. As its Long-term goal, the UCI-ADRC will strive to incorporate the latest in modern neuroscience and cognitive neuroscience to elucidate the nature of circuit dysfunction-mediated behavioral changes. The proposed ADRC infrastructure will support the projects and over 30 other faculty investigators in the ADRC.

DESCRIPTION (Adapted from the application): This proposal aims to establish a new ADRC at UCI which will focus on the basic cellular and molecular mechanisms of brain aging and AD, and seek to identify mechanisms of early pathogenic change and relate these mechanisms to cognitive and behavioral functions. Building upon the existing UCI Institute for Brain Aging and Dementia and continuing commitments by UCI to further develop Alzheimer's Disease (AD) research, the new ADRC will offer an opportunity to link pioneering basic research into early cellular and molecular mechanisms of AD to clinical applications, and apply clinical insights to basic research. The new ADRC will bring several themes to AD research: first and foremost is a cutting edge basic science perspective, second, a dedicated commitment to link basic and clinical studies, and third, an infrastructure to unite the ADRC and pioneer new initiatives that exploit the latest technological advances in bioinformatics. The technological initiatives, coordinated through the Data Management and Biostatistics Subcore (Administrative Core), are directed at fostering investigator-initiated research and bridging clinical and basic research. The four ADRC Projects are directed at investigating mechanisms hypothesized to contribute to early changes in AD brain that lead or contribute to AD progression. Three focus on cellular and molecular mechanisms. While there is always some debate, many investigators recognize three candidate mechanisms associated with the pathogenesis of AD: 1) beta-amyloid accumulation, 2) Inflammatory responses, and 3) Abnormalities in calcium homeostasis. Each of the projects addresses one of these candidate mechanisms. The fourth project will use statistical approaches in contemporary cognitive sciences (multinomial processing tree models) to define deficient sub-processes underlying losses in performance, particularly in early stage subjects. As its Long-term goal, the UCI-ADRC will strive to incorporate the latest in modern neuroscience and cognitive neuroscience to elucidate the nature of circuit dysfunction-mediated behavioral changes. The proposed ADRC infrastructure will support the projects and over 30 other faculty investigators in the ADRC.

DESCRIPTION (provided by applicant): Recent evidence suggests that the deposition of beta-amyloid (Abeta) can be eliminated in a transgenic mouse model that overexpresses human mutant amyloid precursor protein (APP) by immunization with fibrillar Abeta. Further, memory decline appears to be reduced in immunized mice, suggesting a link between Abeta and cognition. We propose to replicate and extend these studies in mice to a higher mammalian model, the aged canine (dog). Over the past 10 years, we have demonstrated that aged canines show a decline in memory and learning and a corresponding increase in Abeta pathology. In addition, recent data support an association specifically between cognitive test scores and the location and extent of Abeta pathology. The questions we hope to answer specifically are: (1) will immunization with fibrillar Abeta reduce the development of cognitive dysfunction in aged canines? (2) will immunization reduce the more highly aggregated, insoluble and long-lived species of Abeta which are typical of both aged human and canine brain? (3) is the reduction of Abeta in the brain through immunization possible in immunologically intact animal models? and (4) are secondary pathologies related to Abeta also reduced (e.g., inflammation, neuritic dystrophy, gliosis, oxidative damage)? To address these issues we propose to study an aged group of dogs that have developed Abeta pathology. Dogs will be immunized with adjuvant-fibrillar Abeta, adjuvant-SAP (serum amyloid protein), adjuvant only, and an untreated control group which will be matched on the basis of cognitive ability. All dogs will undergo extensive baseline testing to evaluate learning (visual discrimination) and memory (object recognition and spatial) ability. After the start of intervention, learning will be evaluated at regular intervals using new visual discrimination tasks. Memory will be re-evaluated using the same object recognition and spatial memory tasks that are designed for repeated testing. At the conclusion of the study, evidence of an autoimmune or inflammatory response will be determined by necropsy. Secondly, the load or burden of several species of Abeta will be quantified using image analysis. Secondary pathological measures are expected to be reduced in parallel with reduced Abeta accumulation. The proposed studies will provide a test of the theory that Abeta causes cognitive dysfunction. Overall, this project should provide unique insight into the efficacy of immunization with fibrillar Abeta and have direct implications for the design of human clinical trials.

DESCRIPTION: (From the Applicant's Abstract): With age neurons are at increasing risk for damage and degeneration. To a large part this is due to the pro-degenerative conditions that develop and have the capacity to initiate damage, necrosis or apoptosis. Many of these conditions build up and exist at sub-lethal levels for periods of time, ranging from days to years. There is much less information on how neurons cause cell loss via necrosis, apoptosis or related mechanisms. There is much less information on how neurons respond to sub-lethal levels of pro-apoptotic inducers. While several factors increase with age and can cause degeneration, tumor necrosis factor (TNF) and amyloid peptide (Abeta) have been implicated in neuronal degeneration and are candidate risk factors for studying the possible effects of sub-lethal pro-apoptotic insults on neurons. In this proposal, we test the hypothesis that TNF and/or Abeta impair neuronal function at concentrations that do not cause overt cell death (sub-lethal levels) by diminishing signal transduction mechanisms induced by growth-and neurotrophic factors, concentrating on effects on BDNF-activated TrkB signal transduction. Recently, TNF has been shown to impair in cortical neurons signal transduction of IGF-1 and phosphatidylinositol 3-kinase (PI 3-K), thereby increasing the risk for neurodegeneration. TrkB also operates via PI 3-K and related pathways. We test the hypothesis that TNF/Abeta interferes with the ability of BDNF to activate TrkB-mediated signal transduction, including the PI 3-K pathway (Aims 1 and 2). This may reduce neuronal survival capacity (Aim 3). We further hypothesize that these insults at sub-lethal levels, reduce critical gene transcription and the regulation of key effectors of brain plasticity. Specifically we hypothesize that these insults may interfere with the ability of BDNF to regulate CREB (Aim 4) and the expression of BDNF (Aim 5). As a result of impaired BDNF-TrkB signaling and BDNF production we hypothesize that the BDNF stimulation of select synaptic proteins will be reduced as will the maintenance and outgrowth of neurites (Aim 6). Together, these experiments may provide support for a mechanism (s) accounting for some of the well-known changes in brain aging and AD, including reduced activity dependent plasticity, synaptic integrity and neuronal survival.

Our overall objective is to use the aged canine to identify effective intervention strategies to reduce age-related cognitive decline and to prevent or reverse cellular and molecular events linked to cognitive dysfunction. We have shown that a diet enriched with antioxidants (AOX), both alone and in combination with behavioral enrichment (ENR), can improve and maintain cognitive function in aged dogs. The current proposal aims to refine our understanding ofthe mechanisms responsible for improved cognition and reduced brain pathology, building on our progress from the current grant period. We have demonstrated that the treatments reduce oxidative damage, improve mitochondrial function, reduce hippocampal neuron loss, and support neurogenesis. Interestingly, our recent data suggest that p-amyloid accumulation was not a primary target of the interventions, consistent with recent studies in humans. Rather, the interventions may be targeting cell health directly by curtailing pro-degenerative pathways driven by protease cascades. In Aim 1, we will follow up on our recent discovery that the interventions attenuate mechanisms of neuronal degeneration, in particular activation of caspase cascades. In Aim 2, we build on the success ofthe AOX and ENR inten/entions by teasing apart and optimizing the original ENR program. We test the hypothesis that long-term exercise intervention is the predominant ENR factor driving improved cognition and reduced age-related brain dysfunction. As in vivo indices of exercise-induced changes in brain function, we will use MRI to assess changes in cerebral blood volume and grey/white matter volume, and evaluate plasma and CSF biomarkers associated with aging and cognitive decline. In Aim 3, we will characterize the cellular and molecular changes induced in the brain by exercise to delineate mechanisms underlying cognitive improvements. A strength of the proposed design will be validation of physiological and cognitive changes assessed in vivo with post mortem histological findings so that the protocol may be applied to humans to monitor the acquired benefit of exercise for each individual. These results will be compared to our previous findings, and will allow the parcelling out of key factors contributing to successful aging.

DESCRIPTION (provided by applicant): This project assembles a unique set of brain specimens to test hypotheses on the relationship of inflammation to synaptic regression and neuron death during normal aging and Alzheimer disease (AD) pathogenesis using microarray technology. Because AD risk is driven by aging, we will evaluate normal brains across the adult life span to identify aging changes in gene expression, which may trigger feedforward cascades leading to irreversible neurodegeneration. To carry out this project a consortium of neuroscientists, neuropathologists and clinicians representing 6 ADCs has been assembled. Frozen, unfixed blocks (250 mg/sample) of the entorhinal cortex/subiculum (EC), hippocampus (HPC), superior frontal gyrus (SFG), and sensory-motor cortex (SMC) will be obtained primarily from five well-established NIA ADC brain banks. The tissue blocks will derive from neuropathologically normal controls, MCI, early mild-moderate AD, and terminal moderate-severe AD (N=10/group). PD cases with dementia but without significant AD pathology (N=10/group) will serve as a disease control. Assignment of cases to groups will be based on common ADC antemortem clinical criteria and postmortem neuropathologic criteria, particularly Braak staging. The experimental groups will be matched for gender and postmortem intervals, none of which will exceed 6 hours, a period during which our preliminary studies suggest that relatively little RNA degradation occurs. Total RNA will be characterized for size distribution and analyzed by Affymetrix gene arrays. Data will be stored in a dedicated hard-drive and searched for changes in specific pathways that may be early markers for and underlying causes of AD study. This proposal will focus on two hypotheses: 1). During aging and mild pathology select genes linked to synaptic function show compensatory changes in the initial stages of cognitive decline and these decline as degeneration evolves. 2). Brain inflammation is a key triggering mechanism resulting in conversion to MCI and/or AD and that inflammatory responses follow or precede synaptic change. Once an initial primary paper is published the overall data will be made available to the field via NACC for various investigators to analyze for the testing their own hypotheses.

[unreadable] DESCRIPTION (provided by applicant): This proposal aims to renew our established Alzheimer's Disease Research Center (ADRC) at the University of California at Irvine (UCI). The ADRC will focus on the basic cellular and molecular mechanisms of brain aging and Alzheimer's disease (AD), seek to identify mechanisms of early pathogenic change and relate these mechanisms to cognitive and behavioral functions. Building upon the existing UCI Institute for Brain Aging and Dementia, a strong group of investigators including many new faculty, and continuing commitments by UCI, the ADRC will offer an opportunity to link pioneering basic research into early cellular and molecular mechanisms of AD to clinical applications, and apply clinical insights to basic research. The ADRC will bring several themes to AD research: first are basic and clinical studies on brain plasticity and compensation - particularly learning and memory, second, a cutting-edge basic science perspective on the mechanisms of neurodegeneration with a commitment to link basic and clinical studies, and third, a new initiative to study clinical, neuropsychological and neuropathological characteristics of the oldest-old (90+ year-olds). The three ADRC Projects are directed at investigating mechanisms hypothesized to contribute to early aging and AD progression. Project 1 focuses on neural correlates of episodic memory in subjects including the oldest-old using cognitive tasks and functional brain imaging. Projects 2 and 3 focus on cellular and molecular mechanisms. Many investigators recognize two candidate mechanisms associated with the pathogenesis of AD: 1) mitochondria! Dysfunction and oxidative damage 2) beta-amyloid accumulation, and neurofibrillary tangle formation. Accordingly, one Project is directed at understanding mitochondria! variations and somatic mutations while the other is devoted to the application of immunotherapy to reduce tau aggregates and tangles. As its long-term goal, the UCI-ADRC will strive to incorporate the latest in modern neurosciences and cognitive neurosciences to elucidate the nature of molecular and cellular dysfunction mediated behavioral changes. The proposed ADRC infrastructure will support the Projects and over 30 other faculty investigators in the ADRC. [unreadable] [unreadable] [unreadable]

human therapy evaluation; antioxidants; vitamin therapy; drug screening /evaluation; combination chemotherapy; drug adverse effect; disease /disorder prevention /control; clinical trial phase I; tocopherols; longitudinal human study; ascorbate; clinical research; human subject; nutrition related tag;

[unreadable] DESCRIPTION (provided by applicant): This proposal aims to renew our established Alzheimer's Disease Research Center (ADRC) at the University of California at Irvine (UCI). The ADRC will focus on the basic cellular and molecular mechanisms of brain aging and Alzheimer's disease (AD), seek to identify mechanisms of early pathogenic change and relate these mechanisms to cognitive and behavioral functions. Building upon the existing UCI Institute for Brain Aging and Dementia, a strong group of investigators including many new faculty, and continuing commitments by UCI, the ADRC will offer an opportunity to link pioneering basic research into early cellular and molecular mechanisms of AD to clinical applications, and apply clinical insights to basic research. The ADRC will bring several themes to AD research: first are basic and clinical studies on brain plasticity and compensation - particularly learning and memory, second, a cutting-edge basic science perspective on the mechanisms of neurodegeneration with a commitment to link basic and clinical studies, and third, a new initiative to study clinical, neuropsychological and neuropathological characteristics of the oldest-old (90+ year-olds). The three ADRC Projects are directed at investigating mechanisms hypothesized to contribute to early aging and AD progression. Project 1 focuses on neural correlates of episodic memory in subjects including the oldest-old using cognitive tasks and functional brain imaging. Projects 2 and 3 focus on cellular and molecular mechanisms. Many investigators recognize two candidate mechanisms associated with the pathogenesis of AD: 1) mitochondria! Dysfunction and oxidative damage 2) beta-amyloid accumulation, and neurofibrillary tangle formation. Accordingly, one Project is directed at understanding mitochondria! variations and somatic mutations while the other is devoted to the application of immunotherapy to reduce tau aggregates and tangles. As its long-term goal, the UCI-ADRC will strive to incorporate the latest in modern neurosciences and cognitive neurosciences to elucidate the nature of molecular and cellular dysfunction mediated behavioral changes. The proposed ADRC infrastructure will support the Projects and over 30 other faculty investigators in the ADRC. [unreadable] [unreadable] [unreadable]

Core A: Administrative Core The Administrative Core will have the responsibility of overseeing the activities of the program and providing support for the interdisciplinary study of behavioral and neural plasticity in the aged. Research studies will include examining inflammation, gliosis, astrocytes, amyloid aggregation and intracellular accumulation. The Core will coordinate the shared use of facilities, services, equipment and supplies by all projects in the program and will coordinate the purchasing and maintenance of animals to meet the needs of all research operations. The Core will also monitor the Tissue and Peptide Resource Core, as well as oversee the availability and access of the ADRC database that incorporates clinical, neuropathological, neuroanatomical, and biochemical data on control and AD tissues. Additionally, the Core will be responsible for organizing meetings and colloquia, overseeing financial matters, and maintaining communication with other AD-related programs at UCI and the Alzheimer's Disease Research Centers of Orange, Los Angeles and San Diego Counties. The Core will also assist in material transfer agreements and oversee animal use/protocols and IRB issues.

[unreadable] DESCRIPTION (provided by applicant): This proposal aims to renew our established Alzheimer's Disease Research Center (ADRC) at the University of California at Irvine (UCI). The ADRC will focus on the basic cellular and molecular mechanisms of brain aging and Alzheimer's disease (AD), seek to identify mechanisms of early pathogenic change and relate these mechanisms to cognitive and behavioral functions. Building upon the existing UCI Institute for Brain Aging and Dementia, a strong group of investigators including many new faculty, and continuing commitments by UCI, the ADRC will offer an opportunity to link pioneering basic research into early cellular and molecular mechanisms of AD to clinical applications, and apply clinical insights to basic research. The ADRC will bring several themes to AD research: first are basic and clinical studies on brain plasticity and compensation - particularly learning and memory, second, a cutting-edge basic science perspective on the mechanisms of neurodegeneration with a commitment to link basic and clinical studies, and third, a new initiative to study clinical, neuropsychological and neuropathological characteristics of the oldest-old (90+ year-olds). The three ADRC Projects are directed at investigating mechanisms hypothesized to contribute to early aging and AD progression. Project 1 focuses on neural correlates of episodic memory in subjects including the oldest-old using cognitive tasks and functional brain imaging. Projects 2 and 3 focus on cellular and molecular mechanisms. Many investigators recognize two candidate mechanisms associated with the pathogenesis of AD: 1) mitochondria! Dysfunction and oxidative damage 2) beta-amyloid accumulation, and neurofibrillary tangle formation. Accordingly, one Project is directed at understanding mitochondria! variations and somatic mutations while the other is devoted to the application of immunotherapy to reduce tau aggregates and tangles. As its long-term goal, the UCI-ADRC will strive to incorporate the latest in modern neurosciences and cognitive neurosciences to elucidate the nature of molecular and cellular dysfunction mediated behavioral changes. The proposed ADRC infrastructure will support the Projects and over 30 other faculty investigators in the ADRC. [unreadable] [unreadable] [unreadable]

AIDS Dementia; AIDS Dementia Complex; AIDS with dementia; AIDS-related dementia; Acquired Immune Deficiency Syndrome related dementia; Actins; Active Follow-up; Age; Aging; Alzheimer; Alzheimer beta-Protein; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimer's amyloid; Alzheimers Dementia; Alzheimers disease; Amyloid; Amyloid Alzeheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Fibril Protein (Alzheimer's); Amyloid Protein A4; Amyloid Substance; Amyloid beta-Protein; Amyloid beta-Protein, Alzheimer's; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antiinflammatories; Antiinflammatory Agents; Autoimmune Diseases; Axon; BDNF; BDNF Receptor; BDNF/NT-3 Growth Factors Receptor; Binding; Binding (Molecular Function); Brain; Brain-Derived Neurotrophic Factor; CREB; CREB1; CREB1 gene; CSBP1; CSBP2; CSPB1; Cell Body; Cell Communication and Signaling; Cell Nucleus; Cell Signaling; Ceramide (lipids); Ceramides; Cessation of life; Cholest-5-en-3-ol (3beta)-; Cholesterol; Chromosome Pairing; Chronic; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive deficits; Cognitive function abnormal; Collaborations; Complex; Condition; Data; Death; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Dementia Complex, AIDS-Related; Dementia Complex, Acquired Immune Deficiency Syndrome; Dementia Due to HIV Disease; Dementia associated with AIDS; Dementia in human immunodeficiency virus (HIV) disease; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Dendritic Spines; Development; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type II; Disease; Disorder; Disruption; Disturbance in cognition; Docking; Dysfunction; EC 2.7; 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65+ years old; Age; Age Group Unspecified; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Amentia; Amyloid Plaques; Attention; Autopsy; Biochemistry; CRISP; Characteristics; Chemistry, Biological; Clinical; Computer Retrieval of Information on Scientific Projects Database; Dementia; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Frontotemporal Dementia; Funding; Genetic; Grant; Institution; Investigators; Morbidity; Morbidity - disease rate; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nerve Degeneration; Nervous; Neuritic Plaques; Neurofibrillary Tangles; Neuron Degeneration; Prevalence; Primary Senile Degenerative Dementia; Rate; Research; Research Personnel; Research Resources; Researchers; Resources; Sampling; Senile Plaques; Source; System; System, LOINC Axis 4; United States National Institutes of Health; age group; amyloid beta plaque; amyloid-b plaque; cored plaque; dementia of the Alzheimer type; diffuse plaque; disease phenotype; frontotemporal lobar dementia; genetic risk factor; human old age (65+); inherited factor; necropsy; neural; neural degeneration; neurodegeneration; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; neuronal degeneration; novel; postmortem; primary degenerative dementia; relating to nervous system; senile dementia of the Alzheimer type; tangle

DESCRIPTION (provided by applicant): Behavioral and Neural Plasticity in the Aged As a general hypothesis, we propose that age-related accumulation of aberrant forms of A?, including various soluble assembly states, as well as fibrillar deposits in the parenchyma and vessels activate innate immune responses, which induce a low level chronic cascade of proinflammatory cytokines and chemokine. The combination of elevated levels of pathological forms of A? and chronic inflammation disrupts trophic factor signaling and cerebrovascular function, and directly contributes to neurodegeneration. We will use novel transgenic model systems and specifically for the 3xTg-AD model which is marked by both AB and tau pathology, generate various crosses and draw comparisons to pathology and mechanisms in human control and AD brain tissues. To address this larger goal, we have assembled a team of investigators with expertise in A?, inflammation and brain pathology and who have a history of working together: Dr. C. Glabe who will investigate A?, A? oligomers and assembly states using conformation specific antibodies in transgenic models and human brain tissues. Dr. C. Cotman will examine the effects of A? assemblies on signal transduction mechanisms and AD pathology. Dr. F. LaFerla, who brings expertise on the development and characterization of novel transgenic model systems, will investigate the role A? and inflammation on the evolution of tau pathology. Dr. A. Tenner will investigate the role of complement on AD pathology and the balance between protective and detrimental effects on the brain and AD. Dr Cribbs will use transgenic models and brain tissues to investigate the mechanism for the development of vascular pathology and along with other program investigators determine how vascular pathology interacts with non-vascular pathology. The efforts of the team will be supported by an Administrative Core (Core A) and a Tissue and Peptide resources Core (Core B). Core B will generate A?, antibodies, assist in the maintenance of transgenic lines and provide well-characterized human brain tissues. PROGRAM PROJECT AS A WHOLE PRINCIPAL INVESTIGATOR: Dr. Cotman is a nationally and internationally recognized leader in aging and Alzheimer research. His excellent credentials for leading this Program are those collected over the years of his very successful directorship, his abilities in the area of leading and encouraging the development of young investigators, and his contribution to our understanding of the neuropathogenesis of Alzheimer's disease and potential therapeutic interventions. REVIEW OF INDIVIDUAL COMPONENTS CORE A - ADMINISTRATIVE CORE, Dr. Carl W. Cotman DESCRIPTION (provided by applicant): The Administrative Core will have the responsibility of overseeing the activities of the program and providing support for the interdisciplinary study of behavioral and neural plasticity in the aged. Research studies will include examining inflammation, gliosis, astrocytes, amyloid aggregation and intracellular accumulation. The Core will coordinate the shared use of facilities, services, equipment and supplies by all projects in the program and will coordinate the purchasing and maintenance of animals to meet the needs of all research operations. The Core will also monitor the Tissue and Peptide Resource Core, as well as oversee the availability and access of the ADRC database that incorporates clinical, neuropathological, neuroanatomical, and biochemical data on control and AD tissues. Additionally, the Core will be responsible for organizing meetings and colloquia, overseeing financial matters, and maintaining communication with other AD-related programs at UCI and the Alzheimer's Disease Research Centers of Orange, Los Angeles and San Diego Counties. The Core will also assist in material transfer agreements and oversee animal use/protocols and IRB issues.

DESCRIPTION (provided by applicant): What are the neural and behavioral profiles that serve successful cognitive aging? Because gene activity provides the fundamental building blocks for cellular function and dysfunction, gene expression patterns must be the cornerstone of successful cognitive aging. One mechanism underlying preservation or maintenance of cognitive function in aging may involve engagement of compensation, a concept that is emerging from human brain imaging data. We propose to identify possible compensatory mechanisms in aging, based on a multidisciplinary approach using microarray analyses to profile gene expression patterns in clinically well-characterized human brain tissues, complemented by animal models to test mechanisms by which physical activity prevents cognitive decline, followed by a translation of the animal data to humans. In Aim 1, a set of clinically and pathologically well-defined human tissues will be used. We hypothesize that in the presence of pathology, compensatory gene expression will be mobilized to help preserve cognitive function. To address this, cases will be divided into cognitive quintiles, from which we will select the top 20th cognitive percentile, representing successful cognitive aging. To identify possible compensatory gene mobilization, we will assess gene expression profiles in the successful aging cohort, comparing gene those with low vs moderate levels of pathology. In addition, maintaining pathology constant at a moderate level, we will assess gene expression profiles across the top 4 cognitive quintiles to identify how gene expression patterns change with declining cognition. We hypothesize that declines in cognition will be reflected in a downregulation of select gene classes and genes, particularly genes linked to synaptic integrity, plasticity and energy metabolism. Various lifestyle factors are emerging as key for successful cognitive aging, in particular, increased physical activity. Thus, in Aim 2, using both human and animal tissue, we will evaluate the hypothesis that physical activity helps maintain successful cognitive aging by engaging compensatory gene mechanisms, particularly in vulnerable populations. In aged animals showing cognitive impairment, we hypothesize that exercise will reverse the impairment and mobilize a gene profile supportive of cognition/plasticity. In transgenic mouse models carrying the ApoE4 gene, a major risk factor for cognitive decline in humans, we test the hypothesis that exercise may be paradoxically more effective in E4 than E3 animals, in improving cognitive function and mobilizing plasticity-related gene expression. Finally, we seek to translate the animal research to a set of human cases where physical activity and cognition have been monitored, using post-mortem brain tissue to analyze brain gene expression patterns in high- active vs. relatively inactive people. Taken together, our project will provide new insight into gene expression profiles in the human that underlie successful cognitive aging, which are currently unknown. PUBLIC HEALTH RELEVANCE: The human population is aging and thus there is a great need to promote successful cognitive aging. Our studies will define the gene expression profiles in the human brain of those who have achieved successful cognitive aging, and determine if exercise will build and strengthen the aging brain through action on gene expression. Accordingly, these studies will help provide a rational for including exercise as a formula to promote successful cognitive health during aging.

DESCRIPTION (provided by applicant): This application seeks to renew the Alzheimer's Disease Research Center (ADRC) at the University of California, Irvine (UCI). Our overall objectives are to elucidate the factors that trigger the onset of AD and its conversion from the prodromal state of MCI, and to define the clinical and pathological features of AD. Our ultimate goal is to identify means to prevent, mitigate and eradicate this disorder. Towards this end, the UCI ADRC proposes four Cores and 3 Projects. The Administrative Core, directed by Dr. Carl Cotman and co- directed by Dr. Frank LaFerIa, will manage, guide and support the ADRC. The Clinical Core (Core 6), directed by Dr. Claudia Kawas, follows the standard cohort (controls, MCI and AD) and two unique human cohorts: (1) Down syndrome subjects, which represents the single largest cause of early-onset AD, and (2) individuals over 90 years, a particularly high incidence dementia group well-represented in the area for inclusion in an autopsy study. The Data Management and Statistics Core, directed by Dr. Dan Gillen, will manage ADRC data and support the Cores and ADRC investigators in standard and novel data analysis. The Neuropathology and Tissue Resources Core, co-directed by Dr. Ron Kim and David Cribbs, will collect postmortem and distribute brain tissues and body fluids from the clinical cohorts. The Core will also support investigator driven translational research with transgenic animal models, beta-amyloid peptides (AP) and conformation specific antibodies to A[unreadable]. The Education and Information Transfer Core, directed by Dr. Ruth Mulnard, will assist in subject recruiting and in education and information among ADRC investigators and the community. To support the overall goals of the ADRC and provide leadership in the field, the UCI ADRC proposes three Projects: 1) Neuroimaging of Hippocampal Subfields in Older Adults &MCI (Project Leader: Craig Stark, Ph.D.);(2) Astrocyte-related molecular mechanisms underlying altered neuronal plasticity in Down syndrome (Project Leader: Jorge Busciglio, Ph.D.) and (3) Neural stem cells to treat and model Alzheimer Disease (Project Leader and new investigator: Mathew Blurton-Jones, Ph.D.). These projects and Cores will interact extensively with other ADRC investigators to continue to build an exciting and productive research environment directed at elucidating the triggers, features and ultimately treatments for cognitive decline and development of AD.

This Project focuses on the mechanisms by which beta amyloid (Aß) accumulation and inflammation (specifically interieukin 1 beta; IL-1ß) impair plasticity and neuronal health. We propose that these molecules interfere with endosomal trafficking of brain-derived neurotrophic factor (BDNF) and its receptor TrkB, leading to impaired neuronal health, function and synaptic plasticity. Our data reveal that IL-1 ß and Aß both interfere with retrograde axonal flow of BDNF-TrkB and impair events downstream from BDNF-TrkB signaling, including nuclear gene transcription. In addition, we found that IL-1ß impairs the stabilization of BDNF-dependent long-term potentiation (LTP) by preventing actin polymerization in spines. These data indicate that Aß and IL-iß deteriorate synapses by targeting both pre and post-synaptic components, impairing signal transduction and synaptic plasticity and placing neurons at risk for degeneration. We propose that impairment of endosomal trafficking is a common mechanism by which Aß and IL-1ß impair retrograde signaling and spine plasticity. Supporting the hypothesis that dysfunctional endosomal trafficking is an important contributor to AD pathogenesis, several recently identified genetic risk factors for AD impact function of endocytotic pathways (e.g., PICALM, BINI, CD2AP). In this proposal, we will evaluate how Aß and IL-1ß impair endosomal trafficking, focusing on BDNF-TrkB trafficking, and investigate how signaling events downstream of BDNF-TrkB are impacted. Specifically, in Aim 1, we will evaluate mechanisms by which Aß and IL-1ß interfere with endosomal trafficking and axonal retrograde transport of BDNF-TrkB.In Aim 2, we will determine if IL-1ß impairs postsynaptic activity-dependent BDNF-TrkB trafficking and plasticity in dendritic spines. We also will eviaute how PICALM can modulate BDNF TrkB trafficking.. Aim 3 will translate the in-vitro data to an in-vivo paradigm, to investigate if IL-1ß impairs hippocampal-dependent learning and if select intervention strategies can protect against the detrimental effects of IL-1ß on endosomal trafficking, and learning. Our project incorporates data sharing and multiple collaborations with the team: e.g., Glabe (effects of Aß oligomeric species on BDNF-TrkB trafficking), LaFeria (IL-1ß, Aß and endocytic dysfunction). Tenner (Clq protection from IL-1ß evoked impairments of BDNF-TrkB F signaling), and Cribbs (impairment of endosomal function by IL-1ß and Aß in endothelial cells).

? DESCRIPTION (provided by applicant): Learning depends on the integrity of synaptic plasticity, and it is hypothesized that the decline in cognitive function with age and Alzheimer's disease (AD) is due to impaired synaptic plasticity. One of the most widely used models for studying molecular mechanisms of hippocampal synaptic plasticity is NMDA-receptor dependent long term potentiation (LTP), a cellular analogue of learning and memory. We propose that isolated synaptosomes, which consist of a presynaptic terminal attached to a postsynaptic unit, can provide a powerful system for the study of synaptic plasticity at a biochemical level. Our approach involves isolating synaptosomes from the hippocampus and chemically inducing long-term potentiation (cLTP) to drive activity-dependent changes at the synapse. We identify activity-induced changes by immunostaining for key markers of plasticity, such as the glutamate receptor subunit GluR1, followed by fluorescence cytometry (flow cytometry) to select synaptosomes with positive GluR1 surface staining, a method we refer to as `Fluorescent Assessment of Chemically-Stimulated Long-Term Potentiation' (FACS-LTP). In this proposal, our goal is to build on our initial data that FACS-LTP can be applied to synaptosomes to investigate activity-dependent biochemical modifications in normal animals, and how these change in aging and with Alzheimer's Disease (AD). In this proposal, we aim to: 1) evaluate if cLTP treatment of synaptosomes engages similar biochemical pathways as occurs in slices and cultures with electrophysiological induction, 2) evaluate if the synaptosome-FACS-LTP approach detects declines in synaptic plasticity with age, AD and in the presence of pathology (specifically focusing on IL-1? driven inflammation), and can be used for drug-screening to identify agents that facilitate or impair synaptic plasticity. Overall, our model system, which uses synaptosomes in combination with LTP to study plasticity, introduces a new functional assay for behavioral studies, mechanistic studies, and screening of pharmaceuticals.

? DESCRIPTION (provided by applicant): Exercise participation is an important determinant of cognitive health, particularly in aging. In fact, sedentary behavior has been singled out as the greatest modifiable risk factor causing cognitive decline and Alzheimer's Disease in the US, and ranks third worldwide. Despite the importance of physical activity and exercise, the exercise parameters that provide optimal cognitive health are not well defined, particularly with respect to the frequency and duration of exercise needed. Our data and others suggest that the exercise conditions that activate the underlying neurobiological mechanisms that enhance cognitive function can be flexible, and allow for intermittent and spaced exercise bouts. We propose the novel hypothesis that exercise establishes a type of molecular memory for the exercise stimulus, which regulates the frequency and duration of subsequent intermittent exercise that is needed to maintain cognitive benefits. The molecular memory remains during a defined temporal window, such that subsequent exercise (even low-level exercise normally sub-threshold to enhance long-term memory formation) can capitalize on the neurobiological events established by the initial experience of exercise, thus maintaining the benefits of exercise on cognitive function. We hypothesize that epigenetic mechanisms are fundamental for the molecular memory phenomenon, and serve to alter transcriptional processes through histone modifications to create stable changes in neuronal plasticity and giving rise to stable changes in behavior. Our goal in this proposal is to define the exercise parameters that establish a molecular memory, investigate the underlying mechanisms that enable exercise to more efficiently promote enhanced cognition, and explore if pharmaceutical manipulation can extend the molecular window established by exercise. Because benefits of exercise for improving cognition, particularly hippocampal function, rely in large part from induction of the key plasticiy molecule `brain-derived neurotrophic factor' (BDNF), we focus on BDNF induction and epigenetic modifications that control BDNF regulation. We propose three Aims. Aim 1 - Determine the effective exercise patterns and molecular memory temporal windows that result in long-term memory formation. Aim 2 - Determine the histone modification patterns resulting from exercise that establish a molecular memory for BDNF expression. Aim 3 - Determine if cognitive benefits of exercise can be prolonged by pharmacological manipulation of the epigenetic molecular memory established by exercise, using a novel selective histone deacetylase 3 (HDAC3) inhibitor. Overall, our research in this proposal will serve as a foundation for ultimately translating to humans the exercise parameters needed to maintain enhanced cognitive function.

Project Summary/Abstract Clinical trials of Alzheimer's disease (AD) therapeutics have had the highest failure rate of any major disease, with only 1 compound approved of 244 compounds tested during 2002-2012 (Cummings, 2014). The majority of these compounds target known pathological processes such as beta amyloid (?-amyloid) processing or neurotransmitter system imbalance, and the failure of these trials highlights the urgent need for new biological approaches to treat AD. One new approach is to target the epigenetic mechanisms that are integral to learning and memory encoding. Histone H3 lysine 9 (H3K9) is a key target for methylation, with di and trimethylation of this site serving as transcriptional repressors. In preliminary data, we have discovered that H3K9 trimethylation (H3K9me3) increases with age in the hippocampus and is associated with cognitive decline in aged and AD transgenic mice. Notably, selective inhibition of the methyltransferase controlling H3K9 trimethylation (SUV39H1) with a newly developed pharmacological small molecule inhibitor (ETP69) dramatically improves hippocampus-dependent memory in aged and transgenic AD mice (but not young mice), opens repressive chromatin structure at genes required for memory formation, increases hippocampal BDNF levels, promotes transcription of NR4a2, and stimulates growth of dendritic spines, thus restoring key mechanisms commonly proposed for synaptic dysfunction with age and AD. This suggests that an approach for treating AD may be to target a specific epigenetic mechanism (H3K9me3) involved in the coordinate regulation of gene expression required for normal brain function. In this proposal we will build on our preliminary data and test the hypothesis that H3K9me3 levels and distribution regulated by SUV39H1 become unbalanced in the aging brain and exacerbate AD-related phenotypes. Such an unbalance may form the basis for the etiological complexity of AD. We will test the possibility that H3K9me3 is a key nodal repression point for cognitive decline associated with aging and AD, and that reducing H3K9me3 restores lost cognition in wild type and AD transgenic mouse models. We propose three Specific Aims: (1) How does H3K9 trimethylation in the hippocampus shift over the lifespan, do H3K9me3 levels on target genes predict declining hippocampus-dependent cognition, and are benefits of SUV39H1 suppression predicated by elevated H3K9me3 levels? (2) Is H3K9me3 accumulation accelerated by AD pathology (?-amyloid, oxidative stress) and is SUV39H1 suppression effective even in the presence of high pathology? (3) Using ChIP-seq and RNA-seq, what are the SUV39H1/H3K9me3 molecular events that drive the effects on cognition? Overall our studies will define a new mechanism controlling cognitive decline in aging and AD and profile an exciting new pharmacological approach to rebalance gene repression patterns and restore cognitive function.

PROJECT SUMMARY/ABSTRACT At present 5.3 million US citizens are affected by Alzheimer's disease and countless others are impacted by age-related cognitive decline. The cost of care in the US is currently more than $220 billion annually, and with the increase in cases will grow to an unsupportable $1.2 trillion annually by 2050.  The loss of cognitive function will impact the quality of life, the available elderly workforce in the nation and our economic viability. We urgently need to discover new prevention and treatment strategies. Biomedical research and the training of a new generation of scientists devoted to studying the mechanisms associated with aging and age-related disorders hold the greatest promise for identifying strategies that allow individuals to age successfully. Our training program focuses on preparation and instruction in the application of molecular and quantitative approaches to the elucidation of the cellular and molecular mechanisms of age-related neurodegeneration, brain plasticity, and learning and memory. We emphasize training on mechanisms but also the discovery and translation of effective therapeutics including lifestyles such as physical activity. Overall, our training program has five primary features and strengths: 1. A team of innovative and scholarly preceptors who have a strong record of accomplishment for training young scholars and an excellent collaborative environment fostering team science 2. A core set of courses on Brain Aging along with seminars and symposia (eg. ReMIND), training on brain pathology through Clinical-pathological case presentations and a mini-clinical internship 3. A unique environment that allows for students from many departments and programs across the campus to have a customized program of study, an opportunity that a single department based program cannot provide 4. Specific training to help trainees reach their individual career goals that will include Training in Communication skills such as our recent training for students on delivering ?elevator pitches? and brief lay descriptions of research 5. An Individual Development Plan (IDP) to prepare them for their own independent careers in the neurobiology of aging, and continual monitoring to ensure they develop broad understanding of the bench to clinic translation of research to improve the lives of the elderly and ensure sustainably healthcare for the nation. Overall, our Training program in Brain Aging is designed to develop a uniquely trained cadre of investigators who over the years will develop successful careers.  

Project Summary / Abstract Alzheimer?s disease (AD) is the most common cause of progressive dementia (memory and cognitive loss) in older adults. Presently, more than 5.5 million Americans may have dementia caused by AD. There is no cure for this debilitating condition. It is increasingly critical that we develop better early diagnostic tools and new treatment strategies for this neurodegenerative disease. Previous gene expression studies using brain tissue and cross-sectional design identify genes whose expression correlates with AD progression. Gene expression is regulated by the cell?s epigenome comprising of DNA methylation, histone modification and non- coding RNAs. We propose to characterize the epigenome of key cell types in neural circuits responsible for learning and memory. Our goal is to determine how the epigenome shapes hippocampal circuit activity and behaviors during AD progression, using the latest single cell genomic technologies coupled with functional circuit mapping and behavioral analysis. We will use two AD mouse models that recapitulate neuropathological features and functional defects observed in human Alzheimer?s. Our guiding hypothesis is that AD neurodegeneration causes significant alterations in the epigenome of cells, including maladaptive changes in accessible chromatin landscape and gene expression programs in disease relevant cell types. This in turn causes defects in specific neural circuit functionality during AD pathogenesis. In Aim 1, we will generate a comprehensive epigenome- and transcription-based cell atlas for hippocampal CA1 and subiculum, and identify epigenomic changes that accompany AD progression in each cell type in AD model mice and age-matched control mice. Single nucleus ATAC-seq (snATAC-seq), single nucleus RNA-seq (snRNA-seq) and the newly developed Methyl-HI in single cells for joint mapping of DNA methylation and chromatin contacts will be key approaches. The proposed work will allow for creation of the first single cell multi-omics atlas of the hippocampal circuits, and will allow us to track the epigenomic changes exhibited by multiple specific cell populations at different AD-like neurodegeneration stages. In Aims 2 and 3, we will investigate the cell subtype specific epigenomic and gene expression basis of neural circuit activities and related memory behaviors in AD model mice of middle age. We will measure epigenomic and behavioral changes in response to genetically targeted ontogenetic hippocampal circuit manipulation and histone deacetylase inhibition. Further, we will determine the beneficial effects of simple behavioral interventions via physical exercise on AD-related epigenomic signatures in Aim 3. Together, our proposed research will provide a new framework to study the molecular underpinnings of neural circuit activities affected during the course of AD pathogenesis. It will also lead to the identification of new therapeutic targets and molecular biomarkers for early detection and better treatment of AD.

Project Summary / Abstract Alzheimer's disease (AD) is the most common cause of human dementia that progressively worsens with age. Sporadic late-onset AD accounts for more than 90 percent of Alzheimer?s cases without clear documented familial history of the disease. However, the vast majority of existing transgenic and knock-in models incorporate disease-causing familial mutations in one or more genes associated with dementias, representing a major limitation. The RFA-AG-21-003 [New/Unconventional Animal Models of Alzheimer?s Disease] highlights the need to develop and characterize naturally occurring ?non-murine models of AD that may represent improved translational potential by better replicating pathological features of the human disease?. We respond to the RFA to apply single cell epigenomic and transcriptomic technologies developed by our team to create cell-type- specific epigenome and transcriptome maps in frontal cortex and hippocampus that are associated with AD-like pathogenesis in two naturally occurring AD animal models: Octodon degus and Canis familiaris. These animals show age-dependent neuropathology and cognitive impairment similar to those observed in human AD, thus they are natural AD models. As both degus and mice are rodents, the studies of long-lived degus will be particularly valuable for a within-mammalian order comparison of which AD gene regulatory pathways are common to spontaneous AD-like features in degus versus different transgenic mouse models. While we generate the resources in alignment with the RFA goals, the proposed research will allow us to develop a comparative analysis to determine conserved epigenetic alterations in the unconventional animal models and bridge our existing databases of mouse models and humans. Maladaptive changes in accessible chromatin accessibility, chromatin organization and gene expression in disease relevant cell types will reveal species- specific and cross-species conserved mechanisms of AD pathogenesis, as well as new targets for AD prevention and treatment. This will provide new insights into the mechanisms of AD pathogenesis in humans. In addition to genome data sharing at the designated NIH depository, resources will be shared and curated at our UCI Center for Neural Circuit Mapping.

Project Summary / Abstract Age-related cognitive decline is an important concern in the United States, as approximately 20% of the US population is expected to be age 65 or older by year 2030. Understanding the molecular mechansims of brain aging to prolong healthy cognitive function is therefore increasingly important as the population ages and older people remain in the work force. Brain cells exhibit profound and heterogeneous changes during aging at molecular and cellular levels. The simple intervention of physical exercise has emerged as a major positive modulator of cognitive function in aging. In response to RFA-RM-20-005, we have formed an interdisciplinary team with expertise in single-cell genomics, neural circuitry, and aging, to investigate age- and physical activity- related changes of 4D nucleome in post-mortem human brain hippocampus cells across the lifespan with single- cell resolution. We hypothesize that cell-type-specific re-organization of nucleome occurs in the human hippocampal brain region during aging and with physical activity. The changes in nucleome in turn control brain epigenome and transcriptome, modulating neural circuit functionality. The ?Methyl-HiC?, a new approach for joint profiling of DNA methylation and chromatin contacts in single cells, combined with ?Paired-seq?, an ultra- high-throughput method for single-cell joint analysis of open chromatin and transcriptome, will be used to interrogate the chromatin architecture along with DNA methylation, chromatin accessibility and gene expression in the human hippocampus. In Aim 1, we will determine changes in nucleome in major cell types of post-mortem human hippocampus across the life-span with 4 age ranges (20?39, 40?59, 60?79, and 80?99 years old). We will further correlate these changes in nucleome with epigenome and transcriptome in each cell type, to identify vulnerable cell types during aging, and uncover potential gene regulatory programs that could be impacted by aging. In Aim 2, we will determine how physical activity modifies and restores nucleome in specific human hippocampal cell types. We will study two age-matched cognitively?healthy cohorts (70-99 years old) with either high level or low level physical activity, as measured by wearable activity monitors. We will correlate restorative effects on nucleome with epigenome and transcriptome. In Aim 3, we will map how aging and exercise alter nucleome in specific hippocampal cell types with highly controlled quantifiable physical activity in the mouse model, for comparison with human data. These mouse studies allow the exercise variable to be investigated in isolation from effects of other lifestyle factors that can affect hippocampal nucleome, which is not possible with human subjects. The proposed research will help to transform our ability to understand the mechanisms of chromatin organization and function in the context of human brain aging.