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.

Public Health Relevance

Alzheimer's disease (AD) is a devastating, common, and growing epidemic without an effective means of prevention or disease-modifying treatment. The proposal will discover and validate novel underlying mechanisms that trigger, resist, and/or promulgate the disease process, and identify promising new protein targets for effective treatments.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project--Cooperative Agreements (U01)
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Study Section
Special Emphasis Panel (ZAG1)
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Refolo, Lorenzo
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Emory University
Schools of Medicine
United States
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Rangaraju, Srikant; Dammer, Eric B; Raza, Syed Ali et al. (2018) Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer's disease. Mol Neurodegener 13:24
Umoh, Mfon E; Dammer, Eric B; Dai, Jingting et al. (2018) A proteomic network approach across the ALS-FTD disease spectrum resolves clinical phenotypes and genetic vulnerability in human brain. EMBO Mol Med 10:48-62
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Rangaraju, Srikant; Raza, Syed Ali; Li, Noel Xiang'An et al. (2018) Differential Phagocytic Properties of CD45low Microglia and CD45high Brain Mononuclear Phagocytes-Activation and Age-Related Effects. Front Immunol 9:405
Bishof, Isaac; Dammer, Eric B; Duong, Duc M et al. (2018) RNA-binding proteins with basic-acidic dipeptide (BAD) domains self-assemble and aggregate in Alzheimer's disease. J Biol Chem 293:11047-11066
An, Yang; Varma, Vijay R; Varma, Sudhir et al. (2018) Evidence for brain glucose dysregulation in Alzheimer's disease. Alzheimers Dement 14:318-329
Rangaraju, Srikant; Dammer, Eric B; Raza, Syed Ali et al. (2018) Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer's disease-related proteins. Mol Neurodegener 13:34

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