Edward H. Koo, MD - US grants

DESCRIPTION: (Investigator's Abstract) Alzheimer's Disease is characterized by the presence of both amyloid plaques and neurofibrillary tangles in cortex. Increasing evidence favors the deposition of amyloid beta protein (Abeta) in plaques as an early and possibly primary event in the pathogenesis of AD, a process that may be related to altered expression or processing of the amyloid precursor protein (APP).To date, the mechanisms that underlie the formation and subsequent deposition of Abeta in brain are unknown. The recent discovery of a constitutive pathway that releases Abeta into media of cultured cells has provided a unique opportunity to understand the mechanism of Abeta formation because of a cleavage within the Abeta domain. Alternatively, APP may be internalized from the cell surface without secretion and directed into the endocytic pathway and ultimately to lysosomes. Results from our preliminary studies suggest that Abeta is generated from endocytosed cell surface APP molecules. These observations lead to the first hypothesis in this proposal: APP that is appropriately targeted to the cell surface and then internalized is the precursors of Abeta released into media. This hypothesis will be examined by two specific aims: 1. localization of the proteolytic steps which generate Abeta and secreted APP in transfected mammalian cells, and 2. characterization of the internalization pathway of APP by morphological and biochemical approaches using normal and mutant APP molecules. Although mutations in the APP gene identified in a few cases of familial AD have provided the strongest link between APP, amyloidogenesis, and the pathogenesis of AD, how these mutations result in disease or altered cellular metabolism is unknown. Building on the first hypothesis, we suggest in the second hypothesis that APP codon 717 mutations, which lie within the transmembrane domain and beyond Abeta, increase Abeta release by altering APP internalization. This hypothesis will be specifically tested in the final specific aim. This investigation represents a detailed study of the APP internalization pathway, which we believe is highly relevant to Abeta production. Results from these studies should provide significant insights into the relationship between APP internalization, APP proteolysis, Abeta release, and familial AD mutations.

Alzheimer's disease is characterized by the presence of both amyloid plaques and neurofibrillary tangles in cortex. Increasing evidence favors the deposition of amyloid Beta-protein (Abeta) in plaques as an early and possibly primary event in the pathogenesis of Alzheimer's disease, a process that may be related to altered expression or processing of the amyloid precursor protein (APP). To date, the mechanisms that underlie the formation and subsequent deposition of amyloid Beta-protein in brain are unknown. The recent discovery of a constitutive pathway that releases ABeta into media of cultured cells has provided a unique opportunity to understand the mechanism of ABeta production. APP is secreted from cells via a pathway that precludes ABeta formation because of a cleavage within the ABeta domain. Alternatively, APP may be internalized from the cell surface without secretion and directed into the endocytic pathway and ultimately to lysosomes. Results from our preliminary studies suggest that ABeta is generated from endocytosed cell surface APP molecules. These observations lead to the first hypothesis in this proposal: APP that is appropriately targeted to the cell surface and then internalized is the precursor of ABeta released into media. This hypothesis will be examined by two Specific Aims: 1) localization of the proteolytic steps which generate ABeta and secreted APP in transfected mammalian cells, and 2) characterization of the internalization pathway of APP by morphological and biochemical approaches using normal and mutant APP molecules. Although mutations in the APP gene identified in a few cases of familial Alzheimer's disease have provided the strongest link between APP, amyloidogenesis, and the pathogenesis of Alzheimer's disease, how these mutations result in disease or altered cellular metabolism is unknown. Building on the first hypothesis, we suggest in the second hypothesis that APP codon 717 mutations, which lie within the transmembrane domain and beyond ABeta, increase ABeta release by altering APP internalization. This hypothesis will be specifically tested in the final Specific Aim. This investigation represents a detailed study of the APP internalization pathway, which we believe is highly relevant to ABeta production. Results from these studies should provide significant insights into the relationship between APP internalization, APP proteolysis, ABeta release, and familial Alzheimer's disease mutations.

Alzheimer's disease is characterized by the presence of both beta- amyloid plaques and neurofibrillary tangles in cortex. Increasing evidence favors the deposition of amyloid beta-protein (Abeta) in plaques as an early and possibley primary event in the pathogenesis of Alzheimer's disease, a process that may be related to altered expression or processing of the amyloid precursor protein (APP). Recent studies have further implicated the longer Abeta species, specifically Abeta peptides of 42 amino acids long (Abeta42) as potentially critical for amyloid deposition and fibril formation. The pathways that lead to the generation of Abeta and Abeta42 have not been clearly defined. The foundation that guides this ongoing project is that processing of APP in the endocytic pathway is important to Abeta production. Accordingly, we have formulated two working hypotheses to direct our continuing research efforts: 1) the APP internalization pathway is the primary route for Abeta production and subsequent release into the medium, and 2) familial Alzheimer's disease mutations alter APP trafficking and, in turn, Abeta production. Three Specific Aims are proposed for the next granting period to test the two working hypotheses. The first Specific Aim examines the role of endocytic processing in the production and release of Abeta42. The second Specific Aim will analyze the relationship between presenilin-1 mutations, APP trafficking and Abeta42 production. In the third Specific Aim, the mechanism by which the APP codon 717 mutations increases Abeta42 production will be explored with regards to the relationship between internalization and gamma-secretase APP cleavage. This investigation of the APP trafficking pathways in a cell culture system will examine fundamental processes that are critical for Abeta (Abeta42) production. Results from these studies may provide important insight into the pathogenesis of Alzheimer's disease.

This new application is to request for five years support to pursue a novel mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD), the most common form of age- related dementing illness. Increasing evidence suggests that NSAIDs have beneficial effects in the treatment or prevention of AD. The mechanisms of NSAID action in AD are unknown although it is widely believed that their anti-inflammatory properties and cyclo-oxygenase (COX) inhibition account for their beneficial effects. Our working hypothesis states that certain NSAIDs are useful in AD therapy by selectively reducing the levels of the pathogenic 42 amino acid species of amyloid beta-peptide (Abeta42) in brain through a cyclo-oxygenase (COX) independent mechanism. In preliminary studies, we found that several NSAIDs reduced the levels of Abeta42 in medium or cultured cells at concentrations above that required for COX inhibition. However, this property was not shared by all NSAIDs, including the newer COX-2 selective inhibitors. Indeed, NSAIDs were able to reduce Abeta42 levels in cell deficient in COX-2 and COX-2 by targeted gene deletions. Importantly, the in vitro results have been confirmed in short term studies of NSAIDs in transgenic mice, thereby demonstrating the physiological relevance of the tissue cultured funding in vivo. Therefore, we hypothesize that Abeta42 reduction and anti-inflammatory effects are parallel mechanisms that together contribute to the apparent efficacy of NSAIDs in AD. The program will rigorously test this hypothesis through three Projects: 1) define the cellular mechanisms that underlie Abeta42 reduction by NSAIDs, 2) identify compounds that maximize the Abeta42 reducing property and test these and existing NSAIDs in vivo, and 3) characterize these Abeta42 lowering effects in human subjects.

DESCRIPTION (provided by applicant): This continuation application is to provide advanced training to predoctoral and postdoctoral fellows in the fundamentals of neuronal plasticity in the aging nervous system. The program has three key features: 1) Academic bridging - A principal focus will be to provide the students and fellows with concepts and research experience which address problems at the interface of basic and clinical problems in aging. This bridging will be reflected in the faculty participating in the program, the trainees admitted to the program, and the structure of the training program itself. Courses, seminars, annual scientific retreat, and co-sponsorships by basic scientists and clinical researchers of trainees will assure that bridging concepts and practice will be emphasized. 2) Life span development - We believe that the aging process is part of a life span process, which should and can be investigated as part of a continuum from birth to death. Many conceptual and practical problems presently being addressed in early development are translatable to late stage aging. This translation of ideas and approaches from studies of development and adult plasticity will be a feature of the program. In general, we believe that investigations of neuronal plasticity are at the very core of understanding late stage aging of the nervous system, since age-related decline often reflects a decrease in neuronal and functional plasticity. Thus, understanding the limits and mechanisms of neuronal plasticity will clearly contribute to further insights into aging and functional decline. In this program, we will encourage the participants to address these age-related aspects of plasticity, disease, and neurodegeneration. 3) Multi- disciplinary - By its very nature, Neuroscience and Aging are multi-disciplinary fields of investigation. The modern neuroscientist is required to understand and use methods and techniques from the full range of biological disciplines and beyond. The faculty in this program have technical expertise in the fields of Molecular Genetics, Protein Chemistry, Cell Biology, Neurophysiology, Systems Analysis, Pharmacology, Cognitive Neuroscience, Computational Neuroscience, and Clinical Neurology. Our goal is to train students and fellows to be able to work and think effectively in several of these areas and will be achieved by providing them a forum for instruction, discussion, and interaction;in so doing, they represent the next generation of neuroscientists who will contribute to the advancement in aging research.

[unreadable] DESCRIPTION (provided by applicant): We have recently found that some non-steroidal anti-inflammatory drugs (NSAIDs) selectively decrease A?42 production by a mechanism that is independent of cyclooxygenase (COX) inhibition. Moreover, an independent study showed that chronic treatment with ibuprofen reduced A? deposition in a transgenic Alzheimer's disease (AD) mouse model. These data suggest that certain NSAIDs selectively reduce A?42, and that this effect rather than the COX mediated anti-inflammatory properties of these compounds might account for their apparent efficacy in reducing risk for AD. In order to explore this hypothesis the synthesis of novel compounds lacking COX activity yet maintaining the ability to lower A?42 is necessary. [unreadable] We have already identified several compounds that lack COX activity, lower A?42, and do so more [unreadable] potently than any of the FDA-approved NSAIDs. Moreover, we have identified a number of NSAID [unreadable] derivatives that unexpectedly raise A?42 and lower shorter A? derivatives including A?38. In [unreadable] addition, we have evidence that NSAIDs directly modulate gamma-secretase cleavage; therefore, we have begun to develop affinity reagents to identify the target responsible for the A?42 altering properties of these compounds. Finally, through systematic modification of several NSAIDs we have begun to identify important structure activity relationships (SAR) that are likely to result in the development of more potent and more selective A?42 lower agents. Based on these findings the aims of the chemical synthesis core are: 1) To produce large quantities of A?42 altering agents that are needed to conduct in vitro and in vivo studies outlined in Projects 1 and 2. 2) To synthesize affinity reagents derived from the A?42 altering agents that we have identified that can be used to identify the target responsible for the A?42 lowering effect of these compounds (Project 1). 3) To synthesize a series of molecules that will provide important information regarding the SAR of the A?42 altering agents. 4) Develop methods to enable detection and quantification of the level of these novel compounds in biological fluids and tissues. [unreadable] [unreadable]

Alzheimer's disease (AD) is characterized by the presence of both beta-amyloid plaques and neurofibrillary tangles in brain. Increasing evidence favors the generation and deposition of amyloid beta-protein (Abeta) in senile plaques as an early and possibly primary event in the pathogenesis of AD. According to this "amyloid hypothesis", Abeta may first target the synapse, initially causing functional perturbations, followed by physical damage and synapse loss, and subsequently neuronal injury. The mechanisms and cellular pathways by which Abeta causes synapse loss and neuronal death are unclear. We have recently demonstrated in preliminary studies that Abeta can accelerate APP multimerization, an event that appears to increase the susceptibility to cell death. This pathway requires an intact APP cytoplasmic region, especially the caspase cleavage site near the C-terminus. These preliminary results have led to the working hypothesis that the APP cytoplasmic domain plays an important contributing role in synapse loss and neuronal death in AD. We propose a model in which one pathway of Abeta- induced cell death involves complex formation with APP, a model which has parallels to the well described FasL-Fas receptor pathway. Importantly, support of this model has been obtained from preliminary analyses of a newly generated line of APP transgenic mice in which the consensus caspase cleavage site in the APP cytosolic tail has been mutated (D664A) so that it cannot be cleaved. High levels of Abeta are generated in the brains of these animals together with Abeta deposits but there is no detectable loss of synapses as determined by synaptophysin immunoreactivity. Theses in vivo observations are entirely consistent with our model in which the synaptic damage in APP transgenic mice is mediated by a pathway that involves both Abeta and the APP cytoplasmic domain. In the first Specific Aim, our goal is to characterize in detail the morphological, electrophysiological, and behavioral phenotype of this newly generated APP D664A transgenic mouse line. In the second Specific Aim, we will initiate studies in human brain samples to correlate levels of caspase cleaved APP with premortem cognition and AD pathology. In addition, we will initiate studies to identify proteins that interact with APP in brain. In sum, results from these proposed experiments should provide important mechanistic insights into synapse loss in brain of AD individuals.

his new application is to request five years of support for an interdisciplinary investigation of hippocampal mechanisms mediating memory. Understanding these mechanisms is vital because their impairment appears to underlie the memory deficits seen in aging and in Alzheimer's disease. From rodents to humans, the hippocampus and adjacent interconnected structures are principally concerned with memory. While the anatomical connectivity within the subfields of the hippocampus is reasonably well delineated, how each of the subfields contribute to learning and memory functions are not clear. At the same time, neurons within the substructures are susceptible to damage and death following injury such as cerebral ischemia, in aging and in certain neurodegenerative diseases such as Alzheimer's disease. In particular, consistent presence of Alzheimer associated pathological lesions in this structure isolates the hippocampus from its cortical connectivity. Consequently, the selective vulnerability of this brain region is likely responsible for the cardinal manifestations of memory impairment in Alzheimer's disease. The working hypothesis that guides this program is that perturbations of axonal and synaptic compartments, either through structural or functional damage, lead to early synaptic dysfunction and result in learning and memory deficits in aging and neurodegeneration. This program will focus on the hippocampus proper, particularly the CA1 and CAS regions with two major goals in mind. First, we will examine the core learning and memory functions of these two subregions of the hippocampus using a novel, selective, and transient inactivation of these neurons through a combination of genetic and pharmacologic means. These manipulations will use exciting new technology developed at The Salk Institute and will allow us to reversibly probe the function of CA1 and CA3 subregions in learning and memory not previously possible. Second, we will investigate the mechanisms responsible for axonal and synaptic changes in this region, particularly in Alzheimer's disease related neurodegeneration. Specifically, we will examine cultured neurons and various mouse models to test several mechanisms that may contribute to hippocampal injury that are initiated by the amyloid beta-protein and the amyloid precursor protein. We propose that both amyloid precursor protein and various proteolytic products, including amyloid beta-protein, contribute in different ways to synaptic and axonal damage in Alzheimer's disease. By bringing together laboratories with unique expertise and background, we propose to probe the hippocampus in memory and in neurodegeneration by a multi-disciplinary approach. Further, a unique and key aspect of this Program is the sharing of common mouse strains, reagents, and vectors to facilitate the collaborative studies proposed in our four Projects.

[unreadable] DESCRIPTION (provided by applicant): A great deal of evidence supports the hypothesis that selective targeting of Abeta42 may be an ideal therapeutic strategy to prevent and possibly treat Alzheimer's disease (AD), the major cause of dementia among the elderly. We have previously reported that select NSAIDS were capable of selectively modulating Abeta42. More recently, we have found that numerous compounds increase Abeta42. Abeta42 modulating agents (generically referred to as gamma-secretase modulators or GSMs) minimally alter total Abeta production but shift the gamma-secretase cleavage site. Abeta42 lowering GSMs increase the production of shorter Abeta peptides and raising agents decrease the levels of shorter Abeta peptides. Current data using novel photoaffinity ligands that modulate Abeta42 cleavage indicate that Abeta42 modulating agents alter production and aggregation of Abeta by binding to a site within the Abeta region of APP carboxyl terminal fragments (CTFs). We hypothesize that binding of the Abeta region of APP CTFs alters the conformation of the APP CTF or its position in the membrane resulting in altered gamma-secretase cleavage, and following cleavage compound binding alters Abeta aggregation. We outline a number of studies to extend our current data that support this hypothesis. We will also evaluate the linked hypotheses regarding the in vivo mechanism of action of Abeta42 lowering NSAIDs and other Abeta42 altering agents. We will perform chronic dosing studies with drug-like Abeta42 lowering and raising agents in APP and BRI-Abeta42 mouse models to evaluate the relative contribution of altering Abeta42 production vs. altering aggregation with respect to effect on Abeta loads and other AD-like pathologies. We will also determine if elevations in shorter Abeta peptides are protective. For these later studies we will use recombinant adenoassociated virus (rAAV) to deliver BRI-Abeta fusion constructs encoding Abeta 1-34, 1-37, and 1-38 to the brain of neonatal APP mice. This methodology creates "somatic brain transgenics" and will allow us to rapidly evaluate the effects of shorter Abeta peptides on Abeta deposition. Effects on Abeta deposition and synaptic transmission will be evaluated. The influence of shorter Abeta peptides on Abeta42 aggregation in vitro will also be evaluated in vitro. These studies should provide additional insight into the mechanisms whereby Abeta42 modulating agents shift Abeta cleavage and how they exert their protective effects in vivo. PUBLIC HEALTH RELEVANCE: A great deal of evidence supports the hypothesis that selective targeting of Abeta42 may be an ideal therapeutic strategy to prevent and possibly treat Alzheimer's disease (AD), the major cause of dementia among the elderly. The proposed studies should provide additional insight into the mechanisms whereby Abeta42 modulating agents shift Abeta cleavage and how they exert their protective effects in vivo. These studies will thereby inform future therapeutic development of this class of potential AD therapeutics. [unreadable] [unreadable] [unreadable]

The responsibilities of the Administrative Core are to coordinate and integrate the activities of the three Projects to ensure maximum cooperation and coordination of efforts among program investigators. Further, the Core will provide administrative and financial support for the Projects on an ongoing basis. The Core will organize the annual visit of the External Advisory Committee to review the scientific progress of the Projects. The Core will interface with the Data Safety and Monitoring Board who will over the safety aspects of the clinical studies proposed in Project 3. Further, the Core will provide fiscal and management oversight of the Alzheimer's Disease Cooperative Study (ADCS) who will be directing the biomarkers study proposed in Project 3. Another goal of the Core is to enrich aging and Alzheimer's disease research by facilitating the dissemination of results and interaction with other investigators at UCSD, Mayo Clinic Jacksonville, and other local institutions. The Administrative Core is responsible for assuring compliance with animal welfare, scientific integrity, and financial policy requirements of UCSD and NIH. Lastly, the Core will be responsible to assembling the annual progress report to NIH.

The amyloid hypothesis states that altered Abeta production or clearance leading to gradual accumulation of aggregated Abeta, which in turn initiates the cascade of events leading to Alzheimer's disease. Increasing evidence supports the concept that the highly amyloidogenic Abeta42 isoform is the pathogenic species. Consequently, selective targeting of Abeta42 may be an excellent anti-amyloid strategy for Alzheimer's therapeutics. In the current funding cycle, we have reported that a subset of nonsteroidal anti-inflammatory drugs (NSAIDs) selectively lower Abeta42 while increasing shorter Abeta species without altering overall Abeta levels, an activity which we term gamma-secretase modulating action. Further, these findings led us io hypothesize that this activity may in part explain the apparent AD risk reduction in chronic users of NSAIDs. Thus, NSAIDs represent the prototypic members of a class of gamma-secretase modulators [GSM) that selectively lower Abeta42 in vitro and in vivo. We also provided preliminary characterization of its potential mechanism of action, which we now believe is centered on the gamma-secretase complex itself, including the APR substrate. In the next funding cycle, we hypothesize that this gamma-secretase modulating activity may target the initial epsilon-cleavage site, which appears to precede and possibly predict the cleavage of various Abeta peptides at the gamma-site. We will test this hypothesis in cultured cells and with in vitro membrane preparations. Further, in studies in collaboration with Project 2, we will examine the biology of shorter Abeta peptides that are invariably increased by Abeta42 lowering agents. We will ask whether shorter Abeta peptides are neurotoxic and whether they modulate the toxicity and aggregability of Abeta42 peptide by testing synaptic transmission and synaptic plasticity following exposure to these peptides. Finally, we will test whether combination treatments with Abeta42 lowering GSMs and a second unrelated compound are superior to treatment with single agents in reducing amyloid levels and amyloid associated pathology in APP transgenic mice. We hypothesize that targeting multiple cellular pathways will ultimately be more efficacious than single targets. We hope that our studies will be translated to testing in AD subjects in the future if we can demonstrate synergy with combination treatments.

PROJECT 3: KOO/ROY - ABSTRACT The amyloid precursor protein (APP) is sequentially cleaved by ¿- and ¿-secretases to generate amyloid ¿-peptide (A¿) in the brain - a central player in the amyloid cascade hypothesis. APP cleavage by ¿-secretase-1 (BACE-1) is the rate-limiting step for production of A¿. A¿ is believed to exert its toxicity on neurons while in a soluble and oligomeric state, prior to deposition as insoluble fibrils in brain. Thus, for reasons related to both pathophysiology and therapeutics, understanding mechanisms and pathways of A¿ generation from APP is a major focus of many laboratories. An intriguing aspect of A¿ production is that its release is dependent upon neuronal activity - enhanced synaptic activity results in more A¿ release. Though pathways involved in trafficking and cleavage of APP in neurons are of obvious importance, the vast majority of previous studies on APP/BACE-1 trafficking have been carried out in non-neuronal cells. These findings may not always be applicable to neurons, which are highly polarized and are known to have very different trafficking mechanisms. Furthermore, inferences on how neuronal activity modulates APP processing by BACE-1 require work in neurons. The prevailing view is that at presynaptic terminals, heightened synaptic vesicle recycling that accompanies high synaptic activity results in increased internalization into endosomes of APP where proteolysis by secretases take place. However, our recent studies using live neuronal imaging showed rather surprising results in that APP and BACE-1 normally traffic in distinct vesicles - perhaps preventing unabated cleavage - but converge in dendrites upon activity-induction. This led us to propose a new model whereby neuronal activity brings together APP and BACE-1 in dendrites where the two molecules interact. Only subsequently are these two molecules sorted into axons to distal terminals. Accordingly, this Project will examine a number of predictions that emanate from this working model and will allow us to refine the trafficking pathways of APP and BACE-1 and define how they relate to amyloidogenesis in neurons in an activity-dependent manner. Four Aims are proposed: 1) test the hypothesis that APP and BACE-1 are first sorted to dendrites immediately after biosynthesis, 2) determine the subcellular sites where APP and BACE-1 interact and correlate this to sites of A¿ release, 3) test the hypothesis that APP and BACE-1 are transcytosed from dendrites to axons, possibly in an activity dependent manner, and 4) utilize tissue from the Neuro-pathology Core to assess whether the colocalization of APP and BACE-1 is preferential to the default mode network brain regions which are known to be sites of A¿ deposits. Collectively, results from these studies will provide new insights into the trafficking pathways of APP and BACE-1 and demonstrate how neuronal activity modulates these pathways to enhance APP cleavage and A¿ release.

DESCRIPTION (provided by applicant): Synaptic loss or dysfunction is believed to be one of the major factors responsible for the memory and cognitive deficits seen in Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. According to the amyloid cascade hypothesis, the gradual accumulation in brain of amyloid ?-peptide (A?), derived from the amyloid precursor protein (APP), is hypothesized to trigger the cascade of events that lead to AD. The mechanisms by which A? may initiate these events, which include synapse loss or synaptic dysfunction, are unclear. Recent studies suggested that both amyloid deposition in extracellular space and intracellular neurofibrillary degeneration, the two hallmarks of AD, may progress in a trans-synaptic or anterograde fashion. That is, the spread of AD pathology in brain, as must occur as the disease develops, expands in a manner that is suggestive of neuron-to-neuron progression. If true, this suggests that A?-induced synaptic injury should be initiated by the presynaptic neuron to alter function of the postsynaptic neuron. Indeed, we have recently obtained preliminary data that support this concept. Specifically, impairment of synaptic plasticity is present only when A? is derived from the presynaptic neuron but not in the reverse situation. These novel observations were obtained from transgenic mice that restrict APP expression preferentially to CA3 or CA1 neurons of the hippocampus. These transgenic mice therefore provide the unique opportunity to ask key questions related to neuronal function or dysfunction caused by local production and release of A? in brain. These questions cannot be addressed with existing transgenic mice where there is pan-neuronal expression of APP at high levels or the recently developed mice with expression restricted to entorhinal cortex. This application will examine the degree to which injury to synaptic function or neuronal circuits develops with respect to the neuronal population where A? is produced. Specifically, we will utilize transgenic mice with spatial and temporal control of APP expression directed to neurons in CA1, CA3, or dentate gyrus by using transgenic mouse lines that express Cre recombinase in CA1, CA3, or dentate gyrus granule cells, respectively. In addition, we will test the reversibility of synaptic and circuit dysfunction in these mouse lines as well as in the original tTA/tet-APP line. Two Aims are proposed: 1) we will explore whether behavior, biochemical, and morphological changes accompany the impairment in synaptic plasticity initiated by A? released from pre- vs. postsynaptic neurons and whether these functional changes become irreversible with age and 2) assess neuronal dysfunction in these mice by measuring field potentials and place cell firing patterns. Collectively, results from these studies using selective and reversible APP expression in subregions of the hippocampus will provide fresh insights into A?-induced neuronal dysfunction in vivo.

PROJECT SUMMARY/ABSTRACT This new application for an institutional T32 program is designed to provide advanced translational research training on Alzheimer's disease and AD related dementias (ADRD). This proposal builds on the outstanding research and training environment of UCSD and participating neighboring institutions (The Salk Institute, Sanford-Burnham-Prebys Institute, and The Scripps Research Institute) as well as leveraging the resources of the UCSD Alzheimer's Disease Research Center, the AD Collaborative Study, and other affiliated programs. To take advantage of the unique opportunities of our research community, we will offer focused but also multidisciplinary approaches to training four pre- and four postdoctoral (MD, PhD, or MD/PhD) trainees to prepare them to tackle the challenges of ADRD due to population aging. The program has three key features: 1. Academic bridging - A principal focus will be to provide the predoctoral students and postdoctoral fellows with concepts and research tools necessary to address issues at the interfaces of basic, translational, and clinical questions in ADRD research. This bridging will be reflected in the diverse interests and expertise of the participating faculty, the nature of the projects proposed by the trainees, and the training plan itself which includes formal didactic teaching and less formal seminars, journal clubs, interactive sessions with faculty, and scientific retreat. 2. Multidisciplinary Approach - By its very nature, neurosciences is a multidisciplinary field of investigation. The training faculty brings to this Program expertise, experience, and technical knowledge in a variety of approaches and disciplines. Our goal is to train future investigators who are to work and think effectively in several of these areas. This will be achieved by choosing the best faculty, by bringing together trainees and mentors who are open to interdisciplinary exchange of ideas and approaches, and providing them a forum for instruction, discussions, and interactions. In addition, we hope to draw into the ADRD community faculty members who have recently expanded their research efforts into ADRD or who have expertise in related areas or in technologies that can expand the scope of ADRD research. 3. Mentorship ? An integral aspect proposed for this Training Program is the attention to mentorship. In addition to the trainee's own research mentor/supervisor, each trainee will select a co-sponsor chosen to provide more multidisciplinary input and oversight into his/her research. Junior faculty members will also be assigned a mentor chosen from the Executive Committee of the Training Program to provide advice and support in order to advance their academic trajectory and enhance the success of their laboratory trainees.