Elizabeth Head - US grants

[unreadable] DESCRIPTION (provided by applicant): During aging, there are a number of brain changes that may contribute to neuronal dysfunction and impaired cognition. Higher animal models are essential for understanding the molecular and cellular basis of brain aging. We have been using the aged canine (dog) model to identify key interventions and molecular mechanisms of brain aging. Age-dependent decline in memory and learning along with the progressive accumulation of oxidative damage, neuron loss and 2-amyloid (A2) deposition occur in the aging dog brain similar to that in the human. Canine A2 is identical to human A2, accumulates endogenously at levels similar to human and A2 plaque loads are correlated with cognitive function. Thus, this model system is useful for exploring links between aging, oxidative damage, A2 and cognition. We have used a dietary and an environmental enrichment intervention to determine if these can improve cognitive function singly and in combination. We have demonstrated that an antioxidant and mitochondrial co-factor dietary intervention improves learning and maintains cognitive function over a 2.8 year period of time in aged dogs. Along with improved learning we observe decreased A2 in antioxidant treated dogs and decreased oxidative damage using proteomics approaches. We have further shown that behavioral enrichment can also improve cognition but this occurs via a non- A2/plaque mechanism as A2 seems unaffected. Importantly, beneficial cognitive effects of the antioxidant diet or behavioral enrichment treatments alone were further enhanced when combined. At present, the molecular targets of each treatment and convergence points between the two treatments that lead to additive neuronal function improvements have yet to be established. The primary objective of this application is to take advantage of newly available technologies (Affymetrix Canine Genome Arrays) and utilize brain tissues from these same animals to further establish and map the neurobiological mechanisms underlying the cognitive improving effects of each treatment and the combined treatment. To accomplish these objectives the following aims are proposed: (1) To profile gene expression changes in the temporoparietal cortex as a function of age in dogs and; (2) To profile gene expression changes in aged dogs provided with either or both an antioxidant-enriched diet and behavioral enrichment. Further understanding of the pathways engaged by these two interventions may lead to new research hypotheses, treatments and outcome measures that may be directly translated to human clinical trials. PUBLIC HEALTH RELEVANCE: Profiling gene expression changes as a consequence of antioxidant diet and behavioral enrichment interventions in aged canines will allow us to identify and optimize new therapeutics for improving cognition in both normal aging individuals and those with Alzheimer's disease. [unreadable] [unreadable] [unreadable]

Cote B: Tissues and Peptides The Tissue and Peptide Core plays a key role in providing dedicated high quality peptides and antibodies, appropriately aged transgenic mice and human autopsy specimens to support research dedicated to the study of the role of A|3 assembly states and neuroinflammation in pathological aging. To achieve these goals, the Tissue and Peptide Core has 5 aims. (1) Produce and provide well-characterized peptides, antibodies and A(3 assays to individual investigators. All program investigators require either A0 peptides or preparations of different types of A(3 assembly states in addition to novel antibodies. The Core will provide standardized measures of soluble and insoluble ApM-40/Apl-42 and, A(3 and neurofibrillary tangle "loads". (2) Generate and maintain transgenic animals and archived transgenic mouse brain tissue samples for use by Program investigators. The use of animal models of human brain aging to facilitate the testing of specific hypotheses is critical to the success of all of the proposed projects. Animals will include the Tg2576, the 3xTg-AD and the ILlraKO mouse lines. (3) Assist in the collection of standard learning and memory data from transgenic animals. The Core will provide training to personnel on how to apply a standardized battery of learning and memory tasks selected to detect functional improvements or impairments in transgenic animals. This optimizes the sharing of behavioral data across individual hypothesis-driven experiments proposed in individual projects. (4) Provide dedicated clinically and neuropathologically characterized human brain samples for use by Program investigators. Brain tissue samples from nondemented healthy aging individuals, patients with Alzheimer's dementia, vascular dementia, mild cognitive impairment and adults with Down syndrome will be collected as they come to autopsy and specific samples will be reserved for Program investigators. Leptomeningeal samples will be acquired on new autopsy cases. (5). Maintain a database of quantitative variables and of resource use to be shared among Program investigators. The Core serves to collate and integrate quantitative neurobiological from human and animal tissues and behavioral data from mice that are provided to Program investigators to allow the seamless integration of data from individual research Projects.

DESCRIPTION (Provided by Applicant): Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) in their 40th year. However, dementia may not develop until up to a decade later, and some people remain cognitively intact. Thus, the investigators seek to follow a group of adults ranging in age from 20-40 years over a five year period of time to identify age and dementia-associated changes in cognition, and in particular focus on frontal lobe function. The aims are four-fold. Aim 1 will cognitively characterize a cohort of adults with DS and follow individuals for a period of five years. Aim 2 will use magnetic resonance imaging to measure white matter integrity on an annual basis in longitudinally followed people. Aim 3 will assay plasma drawn annually from the cohort and measure signaling protein changes to identify biomarkers of AD development and that are also correlated with cognition. Aim 4 will study archived and new autopsy brain samples from DS adults to identify molecular pathways that change prior and during AD development. The outcomes of the proposed studies will contribute to the development of noninvasive biomarkers that will assist in early AD diagnosis in DS and monitor disease progression. Further, novel biomarkers that are mechanistically related to aging, AD neuropathology as well as dementia will also provide outcomes for the design of future therapeutic clinical trials to treat or prevent dementia in DS. PROJECT NARRATIVE: The proposed study will identify new ways in which to detect Alzheimer's disease (AD) in adults with Down syndrome (DS) by monitoring changes in cognitive function, measuring brain changes by magnetic resonance imaging, and profiling patterns of proteins in the plasma. In parallel, autopsy studies of brain samples will help us to understand how noninvasive cognitive, imaging, and blood measures reflect the development of AD in DS. Treatments for AD in DS will be more effective if the disease is detected early, and identifying biomarkers will greatly facilitate the development of therapeutics.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of senile plaques and neurofibrillary tangles. Senile plaques contain the beta-amyloid peptide (A[unreadable]), which is thought to play a causative role in the disease. Thus, a number of therapeutics are being developed that may reduce the production, deposition or enhance clearance of A[unreadable] in the brains of patients with AD. In transgenic mouse models of AD, deposition of A[unreadable] may be prevented or reduced after immunization with fibrillar A[unreadable]1-42. Further, learning and memory is improved by either active or passive immunization with anti-A[unreadable] antibodies. On the basis of work in transgenic mice, a clinical trial (AN1792) was initiated in AD patients who were administered fibrillar A[unreadable]42. Cognitive benefits were reported in this study and autopsy studies show a reduction in brain A[unreadable]. We extended immunotherapy studies into the canine model of human brain aging that naturally develop human-type A[unreadable] and cognitive decline. Aged animals were actively immunized for over 2 years (25 injections in total). Our results in immunized aged beagles showed decreased brain A[unreadable] and improved executive function. We hypothesize that we can improve cognition to a greater extent, and extend cognitive improvements to include multiple domains by combined treatment with an intervention that may restore neuron health after A[unreadable] removal. Thus we propose to combine immunotherapy with behavioral enrichment in aged dogs and target two molecular pathways that may converge to provide additive benefits. We predict aged dogs will show significant cognitive improvements, maintenance of cognition and reduced neuropathology when we combine immunotherapy with behavioral enrichment. Further, the combination treatment will provide larger benefits to cognition and neuropathology than either treatment alone. The canine provides a unique model system in which to develop combinatorial treatment approaches involving immunotherapy for reducing AD pathology and improving cognition that may be more directly translated into human clinical trials. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is associated with progressive cognitive decline and the accumulation of brain pathology. We will use a combination treatment approach to improve cognition and reduce neuropathology in the canine model of aging through immunotherapy and behavioral enrichment, which is an approach that may be directly translated into human clinical trials.

? DESCRIPTION (provided by applicant): Down syndrome (DS) is the major cause of intellectual disability in humans and it is estimated there are over 300,000 individuals with this genetic disorder in the United States. Virtually all DS individuals have sufficient neuropathology for a diagnosis of AD in their 40th year. However, dementia may not develop until up to a decade later and some people remain cognitively intact. In this competitive renewal we propose to continue following (and expand) our cohort of aging adults with DS as well as recruit younger individuals to establish the role of white matter (WM) integrity losses, cerebrovascular dysfunction (CVF) and neuroinflammation on cognitive decline. Aim 1 will continue to cognitively characterize a cohort of adults with DS and follow individuals for a period of 5 years as well as recruit a younger cohort that is pre-AD pathology. Magnetic resonance imaging (MRI) using diffuse tensor imaging will be used to track losses in WM integrity. Aim 2 will use MRI methods to detect cerebrovascular dysfunction by susceptibility weighted imaging, fluid attenuated inversion recovery and arterial spin labeling. Aim 3 will use magnetic resonance spectroscopy and blood biomarkers to detect neuroinflammation as a function of age, AD neuropathology and declines in cognition. Aim 4 will measure proteins and RNA to reflect protein and RNA changes to determine the neurobiological mechanisms underlying losses in WM integrity, CVF and shifts in neuroinflammation in the brains of autopsy cases with DS. We will be able to identify targets for intervention studies (Aim 4) that could be implemented to promote healthy brain aging and would result in cognitive (Aim 1), WM structural integrity (Aim 1), and CVF improvements (Aim 2), and reduced neuroinflammation (Aim 3) in future clinical trials. Identifying the earliest signs of dementia and indicators of individual variation in cognitive decline provides opportunities to implement DS appropriate preventative approaches to slow or halt the development of AD neuropathology and significantly improve the quality of life of DS individuals who are vulnerable to neurodegeneration.

7. Project Summary/Abstract This project uses aging beagles and a longitudinal treatment design to test the potential of a calcineurin (CN) inhibiting strategy in Alzheimer's disease (AD). Beagles are metabolically similar to humans and spontaneously develop amyloid-? (A?) deposition with advanced age. Consequently, the aging beagle model has shown exceptional predictive validity in regard to several high-profile anti-AD drug trials. The molecular target of our treatment strategy, CN, has recently emerged as a key mechanism for AD pathophysiology. Signs of CN hyperactivity are found during early stages of cognitive decline in humans and in mouse models of AD. Studies across numerous laboratories, using a variety of experimental models, suggest that CN activity is both necessary and sufficient for the progression of key AD biobehavioral markers including A? deposition, neurodegeneration, neuroinflammation/glial activation, synapse dysfunction, and cognitive loss. To inhibit CN, we will use tacrolimus, an FDA-approved drug for the prophylaxis of allograft rejection and a second line treatment for numerous immune/inflammatory disorders. In animal models, tacrolimus exhibits potent anti- inflammatory, neuroprotective, and perhaps lifespan extending properties. Moreover, a recent epidemiological study found that the incidence of dementia was strikingly reduced in human kidney transplant patients taking tacrolimus, relative to age-matched subjects in the general population. In this project, 5-6 month old beagles will undergo 1 year of behavioral/cognitive screening. At 6-7 months-of age (prior to the development of significant amyloid pathology), dogs will be sorted into two groups matched for cognitive status. One group will received tacrolimus (.075mg/kg/day, orally) continuously for the next two years, while the other group will receive placebo. Aim 1 will assess multidomain cognition and measure blood and CSF biomarkers (e.g. A? and cytokines) at multiple time points across the tacrolimus treatment period. Aim 2 will use MRI/MRS to measure longitudinal changes in cerebral perfusion, brain metabolism, and structural integrity. Aim 3 will use immunohistochemistry and a variety of biochemical assays to assess AD biomarkers (e.g. A? deposition, glial activation, synapse loss, and neurodegeneration) and CN- related signaling parameters (e.g. cell-type specific expression, CN proteolysis, and NFAT activation) in postmortem brain tissue. These studies will provide a rigorous test of the CN hypothesis of AD and possibly pave the way for investigating CN inhibition has a primary or complimentary treatment strategy in human AD clinical trials.

7. PROJECT SUMMARY/ABSTRACT This is an application for a T32 training grant titled ?Training in Translational Research in Alzheimer's Disease and Related Dementias (TRIAD)? to support 4 predoctoral and 4 postdoctoral fellows. The overall goal of the proposed program is to provide cross-disciplinary training from bench to bedside, to produce a new translational workforce that is critically needed to develop and advance effective treatments for Alzheimer's disease and related dementias. Trainees will receive rigorous and innovative translational research education and training through a 3-cluster multidisciplinary and integrative mentoring program that spans the discovery continuum from molecular/biochemical methods, preclinical translational approaches and clinical research. The thematic focus is on risk factors for Alzheimer's disease and related dementias; these risk factors include cerebrovascular disease, neuroinflammation, Down syndrome, and traumatic brain injury. The training program has 18 faculty mentors with established and extensive interactions and collaborations, and successful track records in training. The faculty mentors encompass diverse areas of expertise from cell & molecular biology, genetics, and data science, through preclinical model systems, therapeutic development, neuroimaging, neuropathology, clinical trials, and longitudinal clinical studies. The majority (13) of these mentors are housed within the University of Kentucky Sanders Brown Center on Aging, which includes a long-standing NIA-funded Alzheimer's Disease Center. All faculty with primary appointments in a Center also have academic appointments in other basic science or clinical departments at the University of Kentucky. Predoctoral trainees will be recruited from our Integrated Biomedical Sciences graduate program and from the MD/PhD program in the College of Medicine, and postdoctoral trainees through targeted advertisement and recommendations from colleagues and other Alzheimer's Disease Centers. In addition to their individualized research program and career development plan, each group of trainees will participate in a series of educational experiences that include a dedicated AD101 course in Alzheimer's disease and related dementias, seminars describing research and clinic ethics, monthly research and career development seminars, journal clubs, Training the Trainers workshops, and grant writing workshops. Each year trainees will be expected to present their research at the annual Markesbery Symposium on Aging and Dementia. Postdoctoral trainees will be provided with additional training opportunities, including: 1) a short off-site externship at another laboratory that conducts Alzheimer's disease research and 2) presentations at the annual College of Medicine Postdoctoral Poster Session. Quantitative and qualitative metrics for evaluation of trainees and the training program will assure a high-quality and effective training experience. The outcomes of our program are intended to nurture highly innovative, well-trained scholars who are dedicated and passionate about finding new approaches to prevent or slow Alzheimer's disease and related dementias.

Research Education Component Project Summary/Abstract The Research Education Component (REC) for the UCI ADRC will provide state of the art training that contributes to the development of a workforce with expertise in Alzheimer disease and related dementias (ADRD). The REC will identify trainees and tailor personalized curricula that leverage training opportunities capitalizing on the full AD ecosystem at UCI. Training will be provide to 3-4 junior investigators (basic science to clinicians) from multidisciplinary backgrounds and leveraging the full and unique resources of the UCI ADRC. Our REC will also practice inclusive excellence and values diversity. Training will include structured workshops and seminars that will provide exposure to the responsible conduct of research and professional skills such as grant writing, networking, work-life balance, etc. Critically important, one-on-one mentoring through ADRC faculty will provide immersion in multidisciplinary and team science approaches to the study of ADRD and the importance of collaboration, innovation and education. The REC will provide a framework for training, mentorship and protected and dedicated time for ADRC training activities. Successful trainees are expected to continue research in ADRD, to facilitate and accelerate possible cures for AD and related dementias and be fully engaged in the ADRC research community.

Overall Abstract Alzheimer disease (AD) is the most common cause of dementia in the general population and the numbers of people living with the disease are rising exponentially. A similar event is occurring in the community of people with Down syndrome (DS) due, in part, to genetic risk (trisomy 21 and lifelong overexpression of APP) leading to overproduction of A?, combined with longer lifespans. The study of DS affords an opportunity to understand the timing and sequence of pathological changes associated with AD. An overarching theme of the Alzheimer?s Biomarkers Consortium ? Down Syndrome (ABC-DS) is to characterize AD in DS, an issue of major and growing significance. Data generated from ABC-DS are necessary to determine if the AD pathological cascade is the same between DS and late onset AD (LOAD) or whether the pathogenic staging has distinct features. Parallels between the two highlights the importance of research with people with DS for advancing our overall understanding of AD, which in turn can form the basis for clinical trials. To that end, ABC-DS assembles an exceptional and highly collaborative research team that will follow a cohort of people with DS to test hypotheses related to 1) how AD in DS may parallel sporadic AD within an amyloid, tau, neurodegeneration AT(N) framework and to identify modifiers of risk of conversion/progression (Project 1); 2) to identify genetic modifiers of the development of AD in DS (Project 2); and 3) to translate outcomes to a precision medicine framework and expedite clinical trials (Project 3). We will acquire harmonized clinical and neuropsychological outcomes (Clinical Core), neuroimaging outcomes (Neuroimaging Core), bio-fluids and genetics measures (Omics Core) and neuropathology data from autopsy (Neuropathology Core). To rapidly disseminate information to our DS communities and to engage underrepresented minorities, we have a Core dedicated to outreach, recruitment and retention (ADDORE Core). Lastly, to build upon nationwide efforts to identify targets for interventions to slow or prevent AD, our Biostatistics and Data Management Core will make high quality data from all aspects of our study available to qualified researchers by distributing outcomes through LONI and ATRI. Following the lead of outstanding established AD networks (ADNI, DIAN), ABC-DS will make a significant contribution to national efforts to improve the quality of life of our aging population through advancing progress toward effective prevention and treatment of AD.

Neuropathology Core Abstract The goal of the Neuropathology Core (NP) is to support research on aging and dementia in DS by systematically collecting, characterizing and disseminating tissues from brain autopsies from clinically characterized participants enrolled in ABC-DS. The NP Core component to the ABC-DS study will provide a final neuropathology diagnosis, perform post-mortem MR imaging, obtain high quality tissue for research purposes, provide an infrastructure for the dissemination of tissue, neuropathology and imaging data and interact with all cores in the ABC-DS. In addition to newly collected brains, in the first 2 years of the study, the NP Core will characterize a legacy cohort of autopsy cases (n=65) to fill in gaps in neuropathology data and acquire novel outcomes. The NP Core will provide critical data in support of Projects 1, 2 and 3. The postmortem imaging data will facilitate the translation of in vivo imaging to neuropathology in a systematic manner. Thus, the NP Core will 1) develop a brain autopsy network, 2) provide neuropathology diagnoses and contribute data to the Biostatistics and Data Management Core; 3) Serve as a repository for tissue and disseminate tissue samples; 4) acquire and share whole slide quantitative digital pathology in support of Projects 1, 2 and 3; 5) acquire post mortem neuroimaging to bridge the gap between in vivo and ex vivo autopsy studies.

Project Summary/Abstract Population aging is leading to a public health crisis in the growing number of people affected by Alzheimer?s disease (AD) and Related Dementias (ADRD). It has been more than 15 years since the last FDA approval for a new treatment for ADRD. To continue the dramatic progress over the last decade in understanding ADRD pathophysiology we will require significant preclinical and clinical translational research to bring candidate therapies to clinical use and grow a therapeutic armamentarium sufficient to curb the public health impact of ADRD. Essential to this success will be a new generation of ADRD scientists, especially scientists with the unique training and skills necessary to design and perform translational research. This training is rarely provided through the traditional course of medical, clinical psychology, basic science, or biostatistical education. As a result, there is a dearth of well-trained ADRD translational investigators. Moreover, there is inadequate diversity among the current group of active ADRD translational investigators, limiting the unique perspectives and team science synergies that could propel the field toward critical solutions. We propose here a new training program in translational ADRD research titled ?Training in Translational ADRD Neuroscience (TITAN)? at the University of California, Irvine (UCI). This new training program will be broadly inclusive of promising graduate students and junior translational scientists, such as medical doctors, clinical psychologists, epidemiologists, biostatisticians, bioethicists, and neuroscientists. We have assembled an outstanding and similarly diverse team of preceptors who will ensure the success of this new training program. The program will develop novel training opportunities in ADRD translational research while also leveraging the considerable scientific and training resources at UCI, including the NIA P30-funded Alzheimer?s Disease Research Center (ADRC), which since April 2020 includes a Research Education Component with complementary objectives. Similarly, the UCI Institute for Clinical and Translational Science (ICTS) is UCI?s NCATS-funded CTSA program that offers synergistic training options to be leveraged, such as the K-club, responsible conduct of research workshops, and KL2 funding mechanisms. We will recruit diverse trainees from multidisciplinary specialties as well as individuals from nationally underrepresented racial and ethnic groups, individuals with disabilities, individuals from disadvantaged backgrounds, and women.