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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AG046161-01
Application #
8605417
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Refolo, Lorenzo
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
Ping, Lingyan; Duong, Duc M; Yin, Luming et al. (2018) Global quantitative analysis of the human brain proteome in Alzheimer's and Parkinson's Disease. Sci Data 5:180036
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
Johnson, Erik C B; Dammer, Eric B; Duong, Duc M et al. (2018) Deep proteomic network analysis of Alzheimer's disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease. Mol Neurodegener 13:52
Guo, Caiwei; Jeong, Hyun-Hwan; Hsieh, Yi-Chen et al. (2018) Tau Activates Transposable Elements in Alzheimer's Disease. Cell Rep 23:2874-2880
Hinkle, Jared T; Perepezko, Kate; Bakker, Catherine C et al. (2018) Domain-specific cognitive impairment in non-demented Parkinson's disease psychosis. Int J Geriatr Psychiatry 33:e131-e139
Abreha, Measho H; Dammer, Eric B; Ping, Lingyan et al. (2018) Quantitative Analysis of the Brain Ubiquitylome in Alzheimer's Disease. Proteomics 18:e1800108
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

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