Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

作     者：Ayyadevara, Srinivas Balasubramaniam, Meenakshisundaram Parcon, Paul A. Barger, Steven W. Griffin, W. Sue T. Alla, Ramani Tackett, Alan J. Mackintosh, Samuel G. Petricoin, Emanuel Zhou, Weidong Reis, Robert J. Shmookler 

作者机构：Cent Arkansas Vet Healthcare Serv McClellan Vet Med Ctr Little Rock AR 72205 USA Univ Arkansas Med Sci Dept Geriatr Little Rock AR 72205 USA Univ Arkansas Med Sci BioInformat Program Little Rock AR 72205 USA Univ Arkansas Little Rock AR 72205 USA Univ Arkansas Med Sci Dept Biochem & Mol Biol Little Rock AR 72205 USA George Mason Univ Ctr Appl Prote & Mol Med Manassas VA 20110 USA 

出 版 物：《AGING CELL》 (老化细胞)

年 卷 期：2016年第15卷第5期

页      面：924-939页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 1002[医学-临床医学] 07[理学] 

基　　金：VA Merit, VA Senior Research Career Scientist Award NIH/NIA [P30 AG028718] NIH [R03 AG043784, P01 AG012411, P01AG012411] Sturgis Charitable & Educational Trust Windgate Charitable Foundation 

主　　题：Abeta(1-42) acetylation (protein) aggregation (protein) Alzheimer (Disease) beta amyloid C elegans microtubule-associated protein tau neurodegeneration neurotoxicity oxidation (protein) phosphorylation (protein) proteomics 

摘      要：Neurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease-specific seed proteins;however, roles of other co-aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer s and control-subject pools using magnetic-bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high-resolution proteomics. Although total detergent-insoluble aggregates from Alzheimer s and controls had similar protein content, within the fractions isolated by tau or A(1-42) pulldown, the protein constituents of Alzheimer-derived aggregates were more abundant, diverse, and post-translationally modified than those from controls. Tau- and A-containing aggregates were distinguished by multiple components, and yet shared 90% of their protein constituents, implying similar accretion mechanisms. Alzheimer-specific protein enrichment in tau-containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co-aggregate with tau were confirmed by precise insitu methods, including proximity ligation amplification that requires co-localization within 40nm. Nematode orthologs of 21 proteins, which showed Alzheimer-specific enrichment in tau-containing aggregates, were assessed for aggregation-promoting roles in *** by RNA-interference knockdown . Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle A, and 12 (57%) rescued chemotaxis disrupted by neuronal A expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by A(1-42). These observations imply shared mechanisms driving both types of aggregation, and/or aggregate-mediated cross-talk between tau and A. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies no