Allan I. Levey - US grants

The major goal of this proposal is to determine the neuroanatomical relationships between muscarinic receptor proteins m1-m5,their respective mRNAs and cholinergic innervation in brain. Cholinergic neurons project widely in the brain and, via stimulation of muscarinic receptors, participate in important neural mechanisms such as learning, memory, arousal, and movement. A family of five muscarinic receptor genes (m 1 -m5) has recently been cloned and sequenced, and mRNAs of four of these receptor subtypes are expressed in brain. Their varied distributions suggest that they are involved in different neural functions. Presently, pharmacological agents are not able to discriminate subtypes of muscarinic receptors clearly. Knowledge of detailed localization of muscarinic receptor proteins m1-m5 is fundamental to understanding cholinergic function in the brain; however, currently there are no methods available for this purpose. This proposal describes the production and characterization of antisera reactive specifically with synthetic oligopeptide sequences and their use in localization of muscarinic receptor proteins m 1 -m5 in rat hippocampus. Oligopeptides corresponding to three predicted unique regions of each receptor subtype will be synthesized and used to immunize rabbits. Antisera will be characterized for ability to bind to receptor subtypes by use of a sensitive coprecipitation assay, immunoblotting, radioligand binding, and immunohistochemistry. These studies will employ homogeneous sources of each receptor subtype, available from cloned cell lines transfected with muscarinic cDNAs ml-m5, in order to define fully the specificities of antisera for each subtype. The ml -m5 receptor proteins will be localized in hippocampus by using monospecific antisera and immunohistochemistical techniques. The distribution of receptor proteins will be compared to that of in situ hybridization of respective mRNAs, as well as the cholinergic nerve terminals by means of immunohistochemistical localization of choline acetyltransferase. Preliminary studies confirm the feasibility of proposed studies by demonstrating specific reactivity of and-peptide antisera against m3 and m4 receptor subtypes in a coprecipitation assay. In situ hybridization studies localizing mRNAs ml, m3, and m4, and immunohistochemical studies of choline acetyltransferase immunoreactivity in hippocampus have also been demonstrated. The anti-muscarinic ml-m5 antisera should be valuable for localizing receptor subtypes in brain, and determining their relationships to central cholinergic systems. This information will provide a rational basis for pharmacological intervention of Alzheimer's Disease, Parkinson's Disease, and other movement disorders as selective muscarinic agents become available.

Recently, a family of five muscarinic acetylcholine receptor genes was identified. The encoded receptors are novel targets for more specific and effective cholinergic therapies for individuals with Alzheimer's disease (AD), but, because of their pharmacological similarities, functions of the subtypes are not well defined. The abundance and localization of individual receptor proteins in the brain, their regulation by cholinergic input, and their involvement in AD have never been studied. In the proposed investigations, subtype-specific polyclonal antisera will be used to evaluate the five native muscarinic receptor proteins in control rat and human brain as well as alterations in receptors in a model of experimental cholinergic deafferentation and in cases of AD. By immunoprecipitation, the relative abundance of proteins will be determined in basal forebrain, neocortex, and hippocampus in rats. By immunocytochemistry, the proteins will be precisely localized and colocalized with cholinergic forebrain neurons. The assessment of receptor number and localization after lesioning of the fimbria-fornix and basal forebrain in rats will provide infomation about the pre- and postsynaptic localization of the subtypes and the cellular and molecular bases for changes induced by deafferentation. Lastly, muscarinic receptor proteins in human brain will be identified, and changes that occur in cases of AD compared to age- and postmortem-matched controls will be measured. These studies will identify the best targets for subtype-specific cholinergic drugs and will provide new neurochemical markers for selective populations of neurons that are potentially at risk in AD.

The objectives of MBRS program at Selma University are, a) to train and motivate undergraduate students who are capable of pursuing their education and career in biomedical sciences, b) to enhance research capability of faculty members of Selma University in biomedical sciences, c) to provide students and faculty with research enrichment activities to develop their biomedical research potential, and d) to attract minority students and faculty into biomedical research. Selma University proposes three research sub-projects and one sub-project related to research enrichment activities. The proposed research activities will train 8 students each year in research related to heavy metal toxicity, phosphoinositide metabolism, intracellular calcium homeostasis, biocomputation, data management, biodegradation of acetonitrile, and relaxation time study of molecular motion in polycrystalline amino acids. The research enrichment activities include seminars, lectures, workshops, summer off-campus research experiences to one faculty and one student, on-campus summer research experience to one advanced freshman student. The program will provide students to a very valuable research experience which will prepare them to meet the demands of graduate studies or careers in biomedical research. Four Selma University faculty will have the opportunity to be involved in research. The expected success of Selma University's MBRS program will be a 'step- forward' in achieving the National MBRS mission of preparing competitive biomedical research scientists who are also ethnic minorities.

The goals of the proposed study are to test the hypotheses that muscarinic acetylcholine receptor (mAChR) subtypes are differentially expressed at unique pre- and post-synaptic sites in key hippocampal circuits and that their expression is altered in Alzheimer's disease (AD). Muscarinic cholinergic transmission in hippocampus is important in learning, memory and attention, and loss of cholinergic input may contribute to cognitive dysfunction in AD. Five mAChR subtypes (m1-m5), encoded by distinct genes, are potentially valuable targets for new cholinergic therapies. Differential expression of ml-m5 receptors in hippocampus suggests a greater complexity in cholinergic modulation of neurotransmission than was previously postulated. A diversity of pre- and post-synaptic cholinergic actions may result from differential cellular/subcellular expression of mAChR subtypes in hippocampus. However, the roles of ml-m5 are poorly understood because the available pharmacological tools do not provide molecular specificity or the spatial resolution necessary to localize the receptors to pre- vs. postsynaptic sites. Determination of the detailed localization of mAChR subtypes in memory circuits and their alterations in AD are necessary first steps toward understanding the molecular basis for cholinergic modulatory actions and for realization of new therapeutic strategies. A panel of mAChR subtype-specific antibodies has been previously developed which has enabled the molecular specificity and high spatial resolution necessary to characterize the synaptic localization of the individual mAChR proteins in brain. In preliminary studies in rat hippocampus, ml-m4 proteins are localized with strikingly different regional, laminar, and cellular distributions in the light microscope. The first aim of these studies will use immuno-electron microscopy to test the hypothesis that mAChR subtypes have distinct pre- and postsynaptic distributions. The second aim will use neuroanatomical tracing techniques (anterograde degeneration and anterograde tracers) combined with immuno-electron microscopy to delineate the pre- and postsynaptic receptor proteins at identified Schaffer collateral synapses in CAL. and at identified perforant pathway and commissural synapses in dentate gyrus. The mAChR proteins localized at these synapses will be visualized using immunoperoxidase and immunogold techniques. The final aim will use light microscopic immunocytochemistry to test the hypotheses that mAChR proteins are expressed in a similar distribution in human and rat hippocampus, and that recently determined alterations in the levels of individual mAChR proteins in AD are due to regional-, laminar-, and cell-specific alterations in their distributions in AD compared to age-matched controls. The results will provide novel insights into the roles of the molecularly distinct mAChR subtypes in rat and human hippocampus, their alterations in AD, and their potential value in developing new pharmacological therapies.

Dopamine and acetylcholine have profound modulatory effects in the primate neostriatum. The receptors mediating these effects are important targets for drug therapies, as dysfunction of these transmitter systems is central to the pathogenesis of Parkinson's disease and other movement disorders. Recently, a large and diverse group of genetically distinct receptor subtypes have been identified. Although their distributions and functions are largely unknown, D1 and D2 (dopamine) and m1, m2 and m4 (muscarinic acetylcholine) are the major receptor subtypes present in the putamen. We have recently developed immunological methods for localization of these dopamine and muscarinic acetylcholine receptors using antibodies to be subtype-specific by immunoblotting and immunoprecipitation of the cloned and native receptors. Preliminary immunocytochemical findings in rat, monkey, and human brain support our hypothesis that individual motor putamen. The first goal of these studies is to delineate the regional and cellular distributions D1, D2, m1, m2, and m4 receptors in monkey and human putamen by light microscopy, and their precise subcellular (e.g., pre- and postsynaptic) distributions in monkeys putamen by electron microscopy. In addition, D1 will be co- localized with the other receptors to determine if the subtypes are expressed in the same, overlapping, or segregated populations of neurons in putamen. The second goal is to determine the relationships of these receptors to putamenal neurons projecting to GPe and GPi, using combined retrograde tracing techniques and receptor immunocytochemistry. These studies will provide direct morphological evidence to support or refute models of receptor subtype segregation between parallel striatal output pathways. The third goal is to determine the synaptic relationships of the receptors wit identified putamental afferent. Afferent from primary and supplementary motor cortices, motor thalamus (centromedian nucleus), substantia nigra, and the midbrain tegmental extrapyramidal area will be identified by anterograde tracing at light and electron microscopic levels. The results will advance our understanding of the molecular pharmacology and synaptic organization of the primate basal ganglia, and will aid in the rational development of more specific and effective drugs, aimed at these molecular targets, for the treatment of Parkinson's disease and other disorders of the basal ganglia.

The Clinical Core will continue to provide a registry of well characterized patients and control subjects to foster clinical and basic scientific research on Alzheimer's disease (AD). To capitalize on the unique strengths and research interests of Emory investigators, the following major cohorts of patients will be recruited and followed: (1) probable AD; (2) Parkinson's disease (PD) without dementia; (3) PD with dementia (PDD); and (4) control subjects without evidence of cognitive or motor impairment. African-American subjects will continue to be recruited through our Satellite Clinic and other sites, maintaining 30% participation in each of our registry cohorts, in parallel with the proportion of African-Americans in our community. Blood will be obtained on patients and control subjects for characterization of mitochondrial DNA, apolipoprotein E genotyping, and other analyses as well as the establishment of lymphoblastoid cell lines by the Molecular Core. Comprehensive and standard neurological and neuropsychological assessment designed to evaluate multiple cognitive and behavioral domains will be performed along with clinical evaluation and quantitative neurophysiological tests of motor function. These data, in combination with molecular and eventual neuropathological information will be a valuable resource for the multidisciplinary group of Emory investigators exploring the heterogeneity of AD, PD, and the overlap among these and other neurodegenerative disorders.

DESCRIPTION: Parkinson's disease (PD) is characterized by a preferential loss of nigrostriatal dopaminergic neurons, and the resultant depletion of dopamine innervation to the striatum is believed to be responsible for the hallmark symptoms of PD. The goal of this study is to test the hypothesis that regulation of the plasma membrane dopamine transporter (DAT) and the neuronal vesicular monoamine transporter (VMAT2) proteins mediate cellular susceptibility in experimental models of PD. It has been proposed that the varying susceptibility observed among different dopaminergic cell groups in idiopathic PD and in MPTP-induced parkinsonism is governed by the relative concentrations of DAT and VMAT2 protein. Specifically, the ratio of DAT to VMAT2, rather than the absolute levels of proteins, controls the cytosolic levels of the putative toxin and thus cellular susceptibility. Here, the applicants capitalize on in vitro and in vivo models recently developed in their laboratories using stable neuronal cell lines and transgenic animals expressing different levels of these transporters to further understand how DAT and VMAT2 expression participate in normal physiological function, as well as disease susceptibility. Therefore, they will test the following hypotheses: Hypothesis I: Stable neuronal cell lines expressing high ratios of DAT to VMAT2 will display increased vulnerability to the parkinsonism-inducing neurotoxin MPP+. Hypothesis II. Transgenic mice expressing high DAT to VMAT2 ratios will exhibit increased susceptibility to MPTP-induced parkinsonism. To test these hypotheses, the applicants propose the following aims: Specific aim 1. Produce stable neuron cell lines that express different ratios of DAT/VMAT2 and determine their susceptibility to MPP+. Specific aim 2. Examine the mechanisms by which MPP+ causes cellular damage in stable cell lines expressing different ratios of DAT/VMAT2 using microphysiology, fluorometry, and confocal microscopy. Specific aim 3. Assess dopamine function and MPTP susceptibility in transgenic mice expressing different levels of DAT and VMAT2 protein. The collective expertise of the participating laboratories will allow successful completion of these aims and thorough testing of these hypotheses, providing crucial data regarding how these transporters regulate both the normal function of dopaminergic neurons and the vulnerability of isolated cells in vitro and in intact animals, furthering our understanding of their role in the pathogenesis of PD. Furthermore, the tools and methods developed in this study will be invaluable to researchers studying other disorders in which monoaminergic function is perturbed, such as cocaine and amphetamine abuse, schizophrenia and Tourette syndrome.

The Alzheimer's Disease Center (ADC) will continue to build upon the resources at Emory to support and foster the growth and quality of Alzheimer's disease (AD). Since its inception in the fall of 1991, the ADC has energized the clinical and research activities of the Emory community. The addition of a Satellite Clinic in urban Atlanta has enabled the ADC to provide research, clinical, and educational opportunities to an underserved, predominantly African American community. The unparalleled clinical and research activities in movement disorders at Emory provide a valuable resource as the ADC examines the overlap and heterogeneity of AD, Parkinson's disease and related dementias. These themes are also synergistic with the unique contributions of Emory investigators in the field of mitochondrial genetics examining mitochondrial abnormalities in neurodegenerative and other disorders. The Administrative and Data Management Core will manage the overall ADC operation and provide the structural foundation for promotion of basic and clinical scientific research. Investigators from Emory Rollins School of Public Health with expertise in study design, data management, and biostatistics will assure quality and integration of data and promote productivity among ADC and other investigators. In a setting of quality patient care, family support, and education, the Clinical Core will provide well characterized groups of AD patients, Parkinson's disease patients with and without dementia, and normal individuals free of cognitive and motor impairment. The high proportion of African American subjects seen through the Clinical Core, paralleling that of our regional population, will enable us to obtain information on dementia in this understudied group. The Neuropathology Core will continue to supply brain and other appropriate tissues from well characterized dementia and control cases to investigators through maintenance of an active brain bank. The Molecular Biology Core will screen for mitochondrial and other genetic abnormalities associated with AD, PD and the overlap syndromes, on well characterized cases seen through the Clinical and Neuropathology cores. The Education and Transfer Core will develop and enhance its innovative educational programs for professionals, caregivers, and other groups. In combination with strong institutional support and the enormous growth of the neuroscience community at Emory, the ADC will serve as increasingly critical role in promoting AD research.

DESCRIPTION (provided by applicant): The Emory MSTP prepares highly gifted and motivated students to pursue careers as physician-scientists and leaders in biomedical research. The seven to eight year training process leads to both M.D. and Ph.D. degrees. The M.D./Ph.D. Executive Committee, comprised of institutional leadership representing the many academic units involved in training, is responsible for oversight of the program. Selection of applicants is highly competitive and is made by the M.D./Ph.D. Admissions Committee after extensive evaluation of prior scholarship and research experience, review of letters of recommendation, and in-depth interviews to assess motivation and determine the potential for success as physician-scientists. The program allows for flexibility in program affiliation, as well as the sequence and duration of clinical or research training, but most trainees pursue the following course of study. Students engage in laboratory research in the summer prior to the first year of Medical School. During the summer between the first and second year of Medical School, they carry out research in their proposed area of study. Following the second year of Medical School, each trainee begins his/her graduate training in advanced study. Trainees pursue dissertation research in a variety of outstanding graduate programs, including any of eight interdisciplinary training programs in the Emory Graduate School Division of Biological and Biomedical Sciences, in the Biomedical Engineering Program offered by the unique combined Department of Biomedical Engineering of Georgia Tech/Emory, in new programs in Biostatistics and Epidemiology offered by the Emory Rollins School of Public Health, or in one of several other scientific disciplines offered by the Graduate School of Arts and Sciences. Each trainee completes at least 14 months of clinical training after defending his/her thesis. The dramatic expansion of the research and clinical infrastructure at Emory and increased institutional support have facilitated the successful growth and development of the MSTP.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] This proposal seeks to continue the training program in Translational Research in Neurology that has been based in the Department of Neurology at the Emory University School of Medicine. Extramural funding from the NIH has grown rapidly, and Emory now ranks 9th among Departments of Neurology in NIH funding, and among the top in neuroscience graduate programs. Having established a formidable research presence in a short period, it is clear that having a formal program to train the next generation of physicians and scientists in neurologic research is extremely important. Because a particular strength of the department's research efforts is translational research, and department faculty have a strong record of bringing therapies "from bench to bedside," our Training in Translational Research in Neurology training program has been extremely successful. We will continue to provide to highly qualified and motivated postdoctoral fellows (M.D.s and Ph.D.s) an outstanding, interactive, and interdisciplinary environment for learning to design and carry out neuroscience investigations that are relevant to clinical disease. In addition, we propose to add 1 pre-doctoral student to this training grant. The training has two main components: First, fellows and students are immersed in an intensive, hands-on laboratory training program. Second, they learn clinical aspects of neurologic disorders, including current concepts of pathogenesis and pathophysiology, current therapy and potential "targets" for experimental therapeutic intervention. Fellows will be trained for a minimum of 2 years, and sometimes 3 years. We anticipate recruiting students and Ph.D.s with research experience but little practical knowledge of neurologic disease, and M.D.s with a firm grasp of clinical neurology but little practical research experience. We will also recruit M.D.-Ph.D.s who have completed clinical training and now wish to "re-tool" for a career in neurological research. The program will be administered by Drs. Allan Levey and Yoland Smith and an Executive Committee. The 52 faculty who will serve as training mentors experienced clinician-scientists or basic neuroscientists working on translational research in the Departments of Neurology, Pharmacology, Genetics, and other clinical and basic departments. [unreadable] [unreadable] [unreadable]

Alzheimer's disease (AD) and Parkinson's disease (PD) are generally considered separate disease entities. However, there is extensive overlap among the clinical and pathologic features, indicating that common mechanisms contribute to neurodegeneration in these disorders. Our preliminary studies from both Emory and Iceland reveal a significantly increased crossed familial risk of AD and PD, suggesting that there are common genetic predispositions in "sporadic" late-onset cases of both diseases. Capitalizing on the ability to examine extended pedigrees in Iceland in collaboration with deCODE Genetics, our exciting preliminary findings demonstrate novel loci associated with both AD and PD., In the proposed collaborative studies between Emory and deCODE Genetics, we test our central hypothesis that a novel susceptibility gene on chromosome 7p contributes to both AD and PD risk in the Emory ADC subjects, and is more strongly associated with those cases with overlapping cognitive and extrapyramidal features. In specific aim 1, we test the association of candidate genes at the chromosome 7p locus with AD subjects in a case-control study using subjects in the Emory ADC. In specific aim 2, we test the association of candidate genes at the chromosome 7p locus with PD subjects in a case-control study using subjects in the Emory Parkinson's Disease Center. In specific aim 3, we propose to perform detailed genotype-phenotype correlations in the Emory AD and PD subjects to understand more precisely the role of the chromosome 7p locus in the clinical manifestations of AD and PD. Together, these aims will test our central hypothesis and advance our understanding of the complex genetics of AD, PD, and overlap syndromes.

SUMMARY The primary goals of the Administrative Core are to maintain, support and monitor the activity of each shared core facility that comprises the Emory Neuroscience NINDS Core Facilities (ENNCF) while ensuring compliance with NIH guidelines. The Administrative core will streamline core activities, facilitate and co- ordinate access to the cores and aid and enhance collaborative interactions amongst established and junior faculty. The Administrative Core will provide for the organizational, financial, and central informational needs of the overall center. These functions will serve to tie the five cores together into a common center, termed ENNCF. The personnel of this core have extensive experience in the management of service centers. The Aims of this core are: 1) to provide administrative oversight for coordinating and scheduling the use of core facilities, maintain, support and update each core-associated website, manage internal budgeting for each core and the entire Center, coordinate and track all purchases, schedule routine equipment maintenance and software upgrades, and prepare and submit progress reports in a timely manner; 2) the Administrative Core, in conjunction with the Steering Committee (comprised of the Directors of the Center, the Directors of each of the Cores, Dean for Research in the Emory School of Medicine, two investigators with qualifying Projects and the grant administrator) will provide a clear and detailed plan for managing ENNCF by ensuring appropriate a) prioritization of services, b) dissemination and access plan for each core, and c) timely generation of activity report for each core. The Administrative core will also ensure fair rates are applied for each core service with timely rate overviews, ensure compliance with NIH guidelines and ensure smooth functioning of each core and resolve conflicting issues that may arise; 3) The Administrative Core will provide an environment that fosters collaborative research utilizing state-of-the-art technologies and multidisciplinary approaches amongst core users by: Hosting seminar presentations by core users and investigators, facilitate (i) accessibility of core services to junior faculty and (ii) interaction with appropriate established investigators, with the goal of providing strong support particularly useful and important for rising, new investigators, develop and maintain an active, dynamic and informative Center website that will be linked to the homepages of other neuroscience related sites and centers on campus; e.g., the Center for Neurodegenerative Diseases (CND). The goal of this website will be to enhance the visibility and effectiveness of the Center while providing details for core services offered. With these activities, the Administrative Core will ensure effective, productive management of the Center as a whole.

DESCRIPTION (provided by applicant): This renewal application focuses on regulation of muscarinic acetylcholine receptors (mAChR) and novel therapeutic approaches to cholinergic involvement in common neuropsychiatric symptoms of human neurological diseases. Cholinesterase inhibitors are the main cholinomimetics available for clinical use, but are only modestly effective and frequently cause adverse effects. Cholinesterase inhibitors act indiscriminately on all members of the mAChR family (M1-M5), but recent evidence suggests that drugs targeted to individual receptor subtypes will be more effective and have fewer side effects. Remarkably, there is also evidence that activation of mAChR subtypes may influence the neuropathology and progression of Alzheimer's disease (AD). The goal of advancing cholinergic therapies through targeting mAChR subtypes has been hampered by several factors, including lack of highly selective drugs, poor understanding of the roles of individual receptors, limited availability of mouse models, and adaptive mechanisms that limit responsiveness during chronic stimulation. However, we and others have made exciting progress overcoming these limitations. This proposal capitalizes on recent progress to test the central hypothesis that activation and antagonism of central M1 receptors play opposing roles in AD. Three Specific Aims will 1) characterize novel drugs that selectively activate M1, 2) evaluate the effects of non-specific and M1-specific cholinomimetics on amyloidogenesis, and 3) evaluate the role of mAChR subtypes in mediating anticholinergic effects and modulating the progression of AD. In order to achieve these Aims, we will employ a blend of pharmacologic approaches using drugs with distinct actions on mAChR, and genetic approaches using transgenic mouse models of amyloidogenesis and knock out mice deficient in individual mAChR subtypes. The results of these studies should substantially advance the goal of developing more effective cholinergic therapies for AD and other neuropsychiatric disorders.

DESCRIPTION (provided by applicant): The Emory Alzheimer's Disease Center (ADC) provides Georgia and surrounding states with outstanding clinical, research, and educational programs. The ADC emphasis on mild cognitive impairment (MCI) is influenced by shared interests in: i) multi-cultural issues in dementia;ii) the clinical spectrum of MCI;and iii) the role of sleep disorders in neurodegeneration. The ADC Cores (Clinical, Neuropathology, Education,also Data Management) build on renowned clinical programs and cutting-edge research. Convergent local developments bring remarkable growth to the ADC, including: one of the nation's fastest growing research enterprises;new leadership focused on neurodegeneration in the Department of Neurology, Center for Neurodegenerative Disease, and Yerkes National Primate Center;outstanding institutional support;close collaborations with the Emory-NIEHS Parkinson's Disease Center and the Center for Health in Aging;a unique industry partnership with deCODE Genetics to discover new susceptibility genes;outstanding clinical programs with a large and diverse patient populations at Wesley Woods Center and Grady Memorial Hospital, with the latter providing services and research opportunities for a predominantly African-American population;and a partnership with Dr. Bernardino Ghetti (Indiana ADC) to jointly operate the Neuropathology Core and enhance research at both institutions. Three cutting edge research projects are closely integrated with ADC Cores: Project 1 (Dr. Stuart Zola) adapts novel, highly sensitive memory tasks developed in non-human primates to ADC Clinical Core subjects;Project 2 (Dr. Allan Levey) tests the association of novel candidate genes for AD and PD, discovered in Iceland, in ADC Clinical Core subjects;and Project 3 (Dr. Junmin Peng) applies state-of-the-art proteomics technologies to MCI, AD, and PD brains characterized in the Neuropathology Core. Collectively, these projects span clinical, translational, and basic research and will advance our understanding of MCI, AD, PD, and related disorders.

[unreadable] DESCRIPTION (provided by applicant): This proposal seeks to establish the Emory Neuroscience NINDS Core Facilities. Neuroscience research has grown dramatically at Emory, with dozens of new investigators receiving NINDS-funding in recent years. The research, based in more than 10 basic science and clinical departments, pursues key issues ranging from the cellular and molecular basis of neural function and mechanisms of neurological disease, to clinical trials of new therapies in stroke and other common diseases. The Emory Neuroscience NINDS Core Facilities will coordinate core activities for 37 NINDS-funded investigators and their 51 qualifying grants, to provide these investigators and other neuroscientists access to a variety of state-of-the-art technologies and approaches that will enhance collaborative, multidisciplinary research. The facility will leverage generous institutional support for personnel, equipment, space and the new Center for Neurodegenerative Disease, to develop or expand the following shared core facilities: a) Proteomics b) Imaging c) Neuropathology/Histochemistry d) Viral Vector and e) Genomics. As directors, Drs. Allan Levey and Ray Dingledine will provide outstanding administrative support for the Center by a) facilitating, coordinating and monitoring access to the cores; b) assisting with budgeting, reporting, and maintaining fiscal responsibility; and c) providing an environment that fosters collaborative research utilizing cutting edge technologies and multidisciplinary approaches. A steering committee comprised of the Directors of the Center and the leaders of the respective Cores will meet at least once every 6 months to assure fair access, provide oversight of the operations of the cores, and to establish priorities and resolve issues. Neurological disorders are major causes of morbidity and mortality. The cores described in this application will facilitate a broad range of NINDS-sponsored research at Emory that is aimed at improving the understanding of disease, and producing new diagnostic approaches, therapies, and prevention. [unreadable] [unreadable] [unreadable]

ADCC; APOE [{C0003595}]; Acetylcholine Agents; Aged 65 and Over; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Amyloid; Amyloid A4 Protein Precursor; Amyloid Protein Precursor; Amyloid Substance; Amyloid beta-Protein Precursor; Amyloid deposition; Animals; Antibody -dependent cell cytotoxicity; Antibody-Dependent Cellular Cytotoxicity; Antigenic Determinants; Apo-E; ApoE; ApoE Receptor; Apolipoprotein E; Autopsy; Binding; Binding (Molecular Function); Binding Determinants; Biochemical; Biological; Blotting, Western; Body Tissues; Brain; Cell Cytoxicity, Antibody-Dependent; Cell/Tissue, Immunohistochemistry; Cells; Cerebral cortex; Cessation of life; Cholinergic Agents; Cholinergic Drugs; Cholinergics; Chromosome Pairing; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Complex; Data; Death; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Deposit; Deposition; Diagnosis; Diagnosis, clinical; Disease Progression; Disturbance in cognition; Dysfunction; ELISA; Elderly; Elderly, over 65; Employee Strikes; Encephalon; Encephalons; Enzyme-Linked Immunosorbent Assay; Epitopes; Foundations; Functional disorder; Gene Expression; Genes; Genetic; Genotype; IHC; Immunohistochemistry; Immunohistochemistry Staining Method; Impaired cognition; LDL-Receptor Related Protein 1; Late Onset Alzheimer Disease; Link; Lipoprotein Receptor; Localized; Low Density Lipoprotein Receptor-Related Protein; Low-Density-Lipoprotein Receptor-Related Protein-1; MT-bound tau; Measures; Molecular; Molecular Interaction; Nerve Cells; Nerve Degeneration; Nerve Unit; Nervous System, Brain; Neural Cell; Neurobiology; Neurocyte; Neurofibrillary Tangles; Neuron Degeneration; Neurons; Numbers; P01 Mechanism; P01 Program; Pathogenesis; Patients; Pattern; Physiopathology; Pittsburgh Compound-B; Play; Population; Primary Senile Degenerative Dementia; Production; Program Project Grant; Program Research Project Grants; Programs (PT); Programs [Publication Type]; Rate; Receptor Protein; Receptor, Apo E; Receptor, Apolipoprotein E; Religion and Spirituality; Research Program Projects; Role; Staging; Staining method; Stainings; Stains; Strikes; Strikes, Employee; Synapses; Synapsis; Synapsis, Chromosomal; Synaptic; Testing; Therapeutic; Tissues; Western Blotting; Western Blottings; Western Immunoblotting; advanced age; alpha-2-Macroglobulin Receptor; alpha2-Macroglobulin Signaling Receptor; amyloid precursor protein; amyloidogenesis; antibody dependent cell mediated cytotoxicity; basal forebrain; basal forebrain cholinergic neurons; base; brain amyloidogenesis; brain control; cDNA Arrays; cDNA Microarray; cholinergic; clinical Diagnosis; cognitive dysfunction; cognitive loss; cognitively impaired; dementia of the Alzheimer type; elders; extracellular; frontal cortex; frontal lobe; geriatric; in vivo; insight; late life; later life; ligand PIB; microtubule associated protein tau; microtubule bound tau; microtubule-associated protein tau; microtubule-bound tau; mild cognitive disorder; mild cognitive impairment; mild neurocognitive disorder; mind control; necropsy; neural degeneration; neurobiological; neurodegeneration; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; neuronal; neuronal degeneration; novel; older adult; older person; pathophysiology; postmortem; primary degenerative dementia; programs; protein blotting; receptor; religious; senile dementia of the Alzheimer type; senior citizen; social role; tangle; tau; tau Proteins; tau factor; trafficking

DESCRIPTION (provided by applicant): The Emory Alzheimer's Disease Research Center (ADRC) provides Georgia and the region with comprehensive clinical, research, and educational programs. This renewal application outlines our success in building an environment that encourages and supports innovative projects with a general theme of discovery and translation of new targets and mechanisms to enable early identification, early interventions, and ultimately prevention of AD. Given the well documented disparities in clinical research participation and burden of disease for AD in the African American community, the Emory ADRC focuses special effort to understand and address inter-individual differences in AD, ranging from ethno-racial factors to personal differences in genetic and protein variation. We benefit from generous institutional support from Emory, one of the nation's fastest growing research academic medical centers, the generous Atlanta community, and a highly collaborative team from more than 20 departments and centers. Five Cores (Administrative, Clinical, Data Management and Statistics, Neuropathology, and Outreach Recruitment and Education), coordinate activities to effectively recruit, evaluate, and engage a diverse cohort of volunteers who actively participate in a wide variety of research studies that aim to better define the trajectory from normal cognitive aging to symptomatic stages of disease. Data from the Cores are captured and stored for distribution to local researchers and for national collaborations. Our biospecimen banks include well-characterized neuropathological case materials, blood and CSF, and DNA. These valuable resources are distributed widely for a variety of approved studies of genetic, molecular, pharmacological, and pathological investigations. The ADRC educational programs reach a broad audience of students, health care professionals, and the public. Three cutting edge research projects are closely integrated with ADRC Cores: Project 1, AD Biomarkers and Endothelial Dysfunction in Caucasians and African Americans, is a longitudinal biomarker study with full integration into the ADRC Clinical Core and OREC, leveraging a unique community based Registry for Remembrance to facilitate recruitment of African Americans; Project 2, A Proteogenomic Approach to Understanding AD GWAS Results, proposes to use state-of-the art targeted gene resequencing and mass spectrometer-based protein sequencing to advance understanding of genetic risk of AD by genetic loci by linking novel gene variants at 20+ recently identified loci directly with the encoded and expressed protein variants in AD brain in an allele specific manner; Project 3, Defining the Properties of Pathogenic A? strains in Alzheimer's Disease, takes an interdisciplinary approach to build on pioneering work showing AD brain extracts are transmissible in animal models, by investigating how structural differences in A? strains from asymptomatic vs. symptomatic stages of AD vary in their seeding and propagation in yeast and animal models.

DESCRIPTION (provided by applicant): This proposal uses proteomics to better understand Alzheimer's disease pathogenesis with a large-scale, unbiased, and direct approach to discover and validate novel disease processes in postmortem AD brain, and to prioritize new targets for early stage therapeutic intervention. The AD proteome mediates the effects of aging, genetics and other risk factors and contains unidentified protein targets for therapies. The approach leverages the strengths of a national team of collaborating AD Centers and associated studies of aging, an innovative proteomics platform, advanced systems biology, and model systems to produce new treatment targets. The first aim will identify novel proteomic targets selectively altered in asymptomatic AD brain. Brains will be analyzed by mass spectrometry (MS), yielding discovery proteomes to compare 1) controls free of AD and other pathologies; 2) asymptomatic controls with AD pathology; 3) non-demented mildly impaired cases with AD pathology, 4) definite AD, and 5) other neurodegenerative diseases. Protein changes in synapses, insoluble aggregates, glial and neuron-specific nuclei, and select posttranslational modifications will be determined. Bioinformatics will be used with available large-scale data to identify potentially druggable targets in key networks and cellular processes. The second aim will validate candidate proteomic targets in postmortem brains from independent community and clinic-based cohorts and determine relationships with clinicopathological features, including cognition. Absolute levels of candidate proteins will be quantified using selected reaction monitoring MS. The third aim will establish links between the validated proteome and AD pathogenesis and druggability. The most promising candidates will be studied for effects on neuronal viability and interactions with Ass and tau using cell culture and drosophila models. These results and other data will drive selection of the most promising candidates to advance to mouse models to assess therapeutic potential.

? DESCRIPTION (provided by applicant): This proposal seeks to maintain and continue support for the Emory Neuroscience NINDS Core Facilities and provide consolidated resources and expertise to NINDS funded projects as well as projects aligned to the NINDS mission of reducing the burden of neurological diseases. There continues to be a great need for these core facilities at Emory given the dramatic growth of NINDS-funded research over the past decade. The Center will coordinate activities to provide shared core services for NINDS funded investigators. Generous institutional support, together with space and other resources available in the Center for Neurodegenerative Disease (CND), will be leveraged to provide access to the following shared cores: (1) Proteomics, (2) Imaging, (3) Neuropathology/Histochemistry, (4) Viral Vectors, and (5) Rodent behavior. These centralized services will enhance collaborative and multidisciplinary research, while providing strong support for junior faculty that is essential to sustain the NINDS mission. In addition to the services, the goal is to also provide outstanding administrative support for the Center by (a) facilitating, coordinating and monitoring access to the cores; (b) assisting with budgeting, reporting, and maintaining fiscal responsibility; and (c) providing an environment that fosters collaborative research utilizing state-of-the-art technologies and multidisciplinary approaches. Moreover, the Steering Committee (comprised of the Directors of the Center, the School of Medicine Dean for Research and the Directors of each of the Cores) will provide oversight of the operations of the cores, ensure compliance with NIH guidelines, establish priorities, and resolve any other issues that may arise. Emory Neuroscience NINDS Core Facilities has been a phenomenal success and is now an extremely valuable asset for the Emory neuroscience community as a whole and in particular for NINDS funded and junior faculty. We also believe it is essential for sustaining and promoting neuroscience investigations and collaborative ventures at Emory University.

SUMMARY/ABSTRACT: Administrative Core (Core A) The Administrative Core of the ADRC provides the infrastructure to support and facilitate the growth of clinical and research activities for Alzheimer's disease and related disorders (AD), capitalizing on the considerable strengths of the neuroscience community at Emory. The Administrative Core will provide the leadership, overseen by the Director, Associate Directors and Administrator, to ensure that all of the resources available at the ADRC are effectively utilized to provide the greatest impact in achieving the Center's goals of discovery and translation of new targets and mechanisms to enable early identification, early interventions, and ultimately prevention of AD. The Administrative Core will address the following Aims: 1) Foster active communication, coordination, integration, and planning of all ADRC activities, including Cores and Projects, an ensure optimal utilization, leveraging and management of resources, 2) Solicit, review, and fund at least three Pilot Projects each year, 3) Enhance AD research, clinical care, and education by maximizing opportunities for interaction with other ADCs and AD investigators, as well as other local, regional, national, and international institutions, agencies, including NIA and industries, and timely submission of data sets to the National Alzheimer's Coordinating Center, and 4) Cultivate an environment that promotes the highest standards for ethics in clinical care and research including compliance with human subjects, animal welfare, fiscal policies and scientific integrity. The ADRC will achieve these Aims by bringing together the many talented multi-disciplinary researchers from the many departments and centers at Emory, foster collaborations with the larger AD research community, engage the community to educate about the importance of research and research participation and foster the training of future ADRC investigators and leaders.

Abstract. The Emory Alzheimer's Disease Research Center (ADRC) provides Georgia and the region with comprehensive clinical, research, and educational programs. This application seeks support to add a Minority Engagement Core (MEC) which will further our success in building an environment that encourages and supports innovative projects with a general theme of discovery and translation of new targets and mechanisms to enable early identification, early interventions, and ultimately prevention of AD. Given the well documented disparities in clinical research participation and burden of disease for AD in the African American community, the Emory ADRC focuses special effort to understand and address inter-individual differences in AD, ranging from ethno-racial factors to personal differences in genetic and protein variation. We benefit from generous institutional support from Emory, one of the nation's fastest growing research academic medical centers, the generous Atlanta community, and a highly collaborative team from more than 20 departments and centers. Five Cores (Administrative, Clinical, Data Management and Statistics, Neuropathology, and Outreach Recruitment and Education), coordinate activities to effectively recruit, evaluate, and engage a diverse cohort of volunteers who actively participate in a wide variety of research studies that aim to better define the trajectory from normal cognitive aging to symptomatic stages of disease. Data from the Cores are captured and stored for distribution to local researchers and for national collaborations. Our biospecimen banks include well-characterized neuropathological case materials, blood and CSF, and DNA. These valuable resources are distributed widely for a variety of approved studies of genetic, molecular, pharmacological, and pathological investigations. The ADRC educational programs reach a broad audience of students, health care professionals, and the public. Three cutting edge research projects are closely integrated with ADRC Cores: Project 1, ?AD Biomarkers and Endothelial Dysfunction in Caucasians and African Americans?; Project 2, ?A Proteogenomic Approach to Understanding AD GWAS Results?; and Project 3, ?Defining the Properties of Pathogenic Aß strains in Alzheimer's Disease?.

DESCRIPTION (provided by applicant): This proposal uses proteomics to better understand Alzheimer's disease pathogenesis with a large-scale, unbiased, and direct approach to discover and validate novel disease processes in postmortem AD brain, and to prioritize new targets for early stage therapeutic intervention. The AD proteome mediates the effects of aging, genetics and other risk factors and contains unidentified protein targets for therapies. The approach leverages the strengths of a national team of collaborating AD Centers and associated studies of aging, an innovative proteomics platform, advanced systems biology, and model systems to produce new treatment targets. The first aim will identify novel proteomic targets selectively altered in asymptomatic AD brain. Brains will be analyzed by mass spectrometry (MS), yielding discovery proteomes to compare 1) controls free of AD and other pathologies; 2) asymptomatic controls with AD pathology; 3) non-demented mildly impaired cases with AD pathology, 4) definite AD, and 5) other neurodegenerative diseases. Protein changes in synapses, insoluble aggregates, glial and neuron-specific nuclei, and select posttranslational modifications will be determined. Bioinformatics will be used with available large-scale data to identify potentially druggable targets in key networks and cellular processes. The second aim will validate candidate proteomic targets in postmortem brains from independent community and clinic-based cohorts and determine relationships with clinicopathological features, including cognition. Absolute levels of candidate proteins will be quantified using selected reaction monitoring MS. The third aim will establish links between the validated proteome and AD pathogenesis and druggability. The most promising candidates will be studied for effects on neuronal viability and interactions with Ass and tau using cell culture and drosophila models. These results and other data will drive selection of the most promising candidates to advance to mouse models to assess therapeutic potential.

There is an unmet need to develop novel biomarkers for Alzheimer?s disease (AD) that are minimally invasive and that more broadly serve as accurate indicators of the underlying pathogenic mechanisms in brain, including impaired neuronal and synaptic function, neuroinflammation, and neurodegeneration. Previous attempts to profile blood proteomes have been hindered by the relatively small number of proteins measured, difficulties linking their expression to AD brain and various disease processes, and poor replicability. The goal of this proposal is to develop a novel plasma protein biomarker platform for AD by deeply profiling the proteomes of matched brain and plasma samples from the same cases, linking the protein networks to the extensive clinical, pathological, and molecular data available in the Accelerating Medicine Partnership for AD (AMP-AD) to nominate candidate plasma protein biomarkers and validate their performance in several independent cohorts. The research will extend and leverage our contributions to the AMP-AD consortium using discovery proteomics and systems biology to generate protein co-expression networks for human post- mortem AD brain. Our initial studies have revealed biologically meaningful groups of co-expressed proteins (i.e., modules) in cortex of AD cases that strongly correlate with key traits such as diagnosis, cognition and neuropathology. The modules identify proteins and pathways involved in AD pathophysiological processes (e.g., synaptic and cytoskeletal dysfunction, inflammation, apoptosis, and others), with stronger trait- associations than in RNA expression networks, high reproducibility across all AMP-AD cohorts, and progressive change from preclinical stages to advanced AD. In the proposed research, our collaborative teams of experts from Emory, Rush, and Oxford will first extend the discovery proteomic analyses in AMP-AD using next generation mass spectrometry and aptamer arrays, increasing the depth of protein coverage several-fold, measuring ~6000 proteins in brain (Aim 1) and plasma (Aim 2) from the same control, AD, and non-AD dementia cases in the Religious Orders Study and Memory Aging Project. An integrative analysis and machine learning will be used to nominate ~100 plasma protein candidate biomarkers most strongly associated with diagnosis, and key clinical, molecular and pathological endophenotypes. The performance of the candidate biomarkers will then be assessed using >2000 samples in three independent cohorts from the M²OVE-AD consortium, the European Medical Information Framework, and Dementia Platform United Kingdom (Aim 3), The results will amplify the impact of the AMP-AD and M²OVE-AD consortia with rapid and full data sharing, and establish an innovative pipeline for discovery and validation of plasma proteomics biomarkers that serve as robust and reproducible indicators of AD, including the dysregulated processes that occur in brain.

DESCRIPTION (provided by applicant): This application seeks funding for a one and a half day mentoring symposium entitled How to Combine Clinical and Research Careers in Neuroscience (CCRCN). The program is sponsored by the Association of University Professors of Neurology (AUPN) (www.aupn.org), together with the National Institute of Neurological Disorders and Stroke (NINDS), the American Neurological Association (ANA) and the Child Neurology Society (CNS). The AUPN is the professional organization for Chairs of Neurology Departments, or Divisions, in accredited medical schools in the United States. Its goal is excellence in the care of patients with neurological disease by providing superior education to neurology trainees and by expanding knowledge about neurologic diseases. Two other professional organizations, the American Neurological Association (ANA) and The Child Neurology Society (CNS), share AUPN's and NINDS' concerns regarding the decline in the number of clinician-scientists, and have joined AUPN and NINDS financially supporting the CCRCN. The CCRCN symposium was first offered in 2003 by the AUPN and NINDS to meet the urgent need for more clinician-scientists, specifically in neurology. In 2005, JAMA reported that less than 2% of all physicians are scientists and, despite increases in research activity and funding, this number continues to drop. When this program began in 2003, the trend showed two decades of increasing biomedical research funding but an alarming 22% decrease in the clinician-scientist workforce; studies showed that more than a third of medical school graduates with MD/PhD do not realize their original goal of becoming active clinician-scientists. The specific aims for this symposium are to: 1) encourage medical students with neuroscience research training to pursue clinical training (with special emphasis on neurology); 2) describe and discuss strategies for successfully melding clinical and research careers; 3) discuss the satisfactions and power of a combined research and clinical career; 4) describe and discuss sources of, and strategies for, obtaining long term training and research support; and 5) provide an opportunity for students to meet and network with academicians who have successfully combined clinical and research careers in neuroscience. Medical students who may be candidates for combined research and clinical careers in the neurosciences are invited to apply to attend this meeting. The ideal candidate will have completed preclinical training and at least one additional year of neuroscience research training. Further consideration is given to students who have completed some required clinical clerkships, as this is the time when many students will be thinking about further clinical training. This symposium is highly relevant to the mission of NINDS, which is to reduce the burden of neurological disease. This laudable goal is directly supported by the CCRCN which strives to increase the number of well-trained clinician-scientists working to find treatments, and even cures, for neurological diseases.

Project Summary There is an unmet need to develop novel therapeutic targets and biomarkers for Alzheimer's disease (AD) and related disorders. During the first phase of consortium, we have added the unique dimension of discovery proteomics to the Accelerating Medicines Partnership (AMP)-AD. We successfully established a high throughput proteomics pipeline and quantified 2-3000 proteins by mass spectrometry (MS) in >1800 postmortem human brains for all AMP-AD teams. Using systems biology tools, we identified highly conserved AD proteomic networks that complement and extend transcriptomic networks, highlighting a set of protein co-expression modules strongly associated with diagnosis, cognition, and neuropathology. Experimental validation of several novel protein targets in these modules confirmed links to neurodegeneration in model systems and in human brain pathology. The overall goal of this renewal application is to fill several key gaps in AMP-AD, which are to enrich and validate the AD brain co-expression network (with coverage of >11,000 proteins, >30,000 phosphosites, and interacting proteins), and better define optimal novel targets for the entire consortium. Using new MS technologies and proven cross-species experimental strategies, we will provide high confidence of module membership necessary to guide therapeutic and biomarker applications. We also will translate these targets into actionable biomarkers to monitor these modules and the respective pathophysiologies in living subjects with the following aims: 1) Integrate proteomics, phosphoproteomics and protein-protein interactions to extend AD networks and define key signaling and pathophysiological pathways linked to AMP-AD targets; 2) Validate predicted network structure for the most promising AMP-AD targets in experimental model systems; and 3) Translate the list of nominated AMP-AD targets including key trait-associated modules and hub proteins into novel CSF biomarkers for AD. The results will amplify the impact of the AMP-AD with rapid and full data sharing and establish an innovative pipeline for discovery and validation of brain proteomics targets and companion CSF biomarkers that serve as robust and reproducible indicators of AD, including the dysregulated processes that occur in brain.

Project Summary/Abstract Drug discovery is an inherently risky endeavor and has proven to be especially so in Alzheimer?s disease (AD). Risk at project inception can be categorized as ?validation risk? (the likelihood that modulation of the target will have a favorable outcome in patients) or ?technical risk? (the likelihood that a tolerable molecule that modulates the target in patients can be discovered). The Open Drug Discovery Center for Alzheimer?s Disease (Open-AD) initiative will create a set of complementary bioinformatic, structural and pharmacologic tools (high-quality chemical probes) to evaluate a diverse set of AD hypotheses in an open discovery environment. Creation of high-quality chemical probes that are active in cellular and animal models of AD versus less explored targets can decrease the technical and validation risk inherent in discovery of new drugs for this disease. Scientists in the Med Chem Core have been successful in developing and sharing freely with the scientific community first-in-class chemical probes unburdened by intellectual property. We are committed to exploring our overarching hypothesis that open drug discovery will accelerate the development of AD medicines through robust and independent evaluation of a diverse set of untested AD therapeutic hypotheses utilizing the most impactful of all tools; a high-quality, cellular and in vivo active chemical probes. Aim 1. Portfolio creation: The Med Chem Core will work closely with the Bioinf and Struct Bio Cores to select a portfolio of novel AD related targets such that 6 targets enter the hit discovery phase each year. Targets will be vetted for the technical risk of probe discovery and prioritized for screening based upon this and the disease validation risk. Aim 2. Hit discovery: The Assay and Screen Core will take the lead on diversity-based HTS for hit discovery. The Med Chem Core will therefore focus on complementary, knowledge-based approaches, such as: virtual screening, focused screening using custom libraries, optimization of fragment-based hits discovered in the Struct Bio Core, structure-guided ligand design, and other rationale approaches. Aim 3. Hit to probe: The Med Chem Core will apply state-of-the-art medicinal chemistry strategies to iteratively design sets of drug-like analogues with physical-chemical properties consistent with CNS penetration. These will be assessed in a hierarchy of assays to address target affinity, selectivity, cellular activity, and in vitro ADME properties. As compounds achieve the desired activity in these assays, they will advance into in vivo assessment of plasma/brain PK and target engagement. Final probes will be extensively characterized to support their MOA and efficacy by the Assay and Screen Core in models of AD. The overall goal of the Med Chem Core is to deliver 3 cellular and 1-2 in vivo probes per year versus novel targets implicated in AD, which will be made freely available to the scientific community. ! 1!

The goal of the parent AMP-AD project is to identify proteomic networks from cortical tissue and identify protein co-expression modules that are strongly associated with diagnosis, cognition and neuropathology. These studies hinge on accurate neuropathologic diagnosis and staging of the brain tissue. These assessments typically involve semi-quantitative evaluation of tissues and there is a need for robust, reliable, and scalable deeper phenotyping to provide a firmer foundation for precision medicine approaches. We have developed the Digital Slide Archive (DSA) platform at Emory, which has been funded through a U24 and U01 grants from the NCI/NIH and has primarily been optimized for Cancer related image analysis workflows. In this project, we propose to deploy and customize a web-based instance of our open source management and visualization platform, the Digital Slide Archive (DSA). Ultimately, we will enable collaborative team science and adapt the existing DSA platform for a neuropathologist?s workflow. This will directly enhance the value of our proteomic work by allowing us to better annotate our brain/proteomic samples. In this proposal, we propose enhancing the user interface of the DSA to better accommodate a neuropathologist?s workflow for reviewing brain tissue, and develop an easily installable Neuropath plugin for the DSA. We will also benchmark and optimize our analysis suite (HistomicsTK) on NP slide sides on local and cloud-based computational resources, and prepare tutorials demonstrating how our tools can be used for ADRD related image analysis tasks. These aims paired with the complementary and synergistic expertise of our informatics, pathology, and engineering will aid in development of robust, scalable, reliable, and sharable platforms to provide a foundation for innovative transformative science addressing a critical unmet need in neurodegenerative disease research.