title: Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls.
abstract: 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 Aβ1-42 pulldown, the protein constituents of Alzheimer-derived aggregates were more abundant, diverse, and post-translationally modified than those from controls. Tau- and Aβ-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 in situ methods, including proximity ligation amplification that requires co-localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer-specific enrichment in tau-containing aggregates, were assessed for aggregation-promoting roles in C. elegans by RNA-interference 'knockdown'. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ 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 Aβ1-42 . These observations imply shared mechanisms driving both types of aggregation, and/or aggregate-mediated cross-talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, 72205, USA. AyyadevaraSrinivas@uams.edu.|Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. AyyadevaraSrinivas@uams.edu.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
authors.affiliation: Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.|BioInformatics Program, University of Arkansas for Medical Sciences and University of Arkansas at Little Rock, Little Rock, AR, 72205, USA.
authors.forename: Meenakshisundaram
authors.initials: M
authors.lastname: Balasubramaniam
authors.affiliation: Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Parcon
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, 72205, USA.|Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Barger
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, 72205, USA.|Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
authors.forename: W Sue T
authors.initials: WS
authors.lastname: Griffin
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, 72205, USA.|Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
authors.forename: Ramani
authors.initials: R
authors.lastname: Alla
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Tackett
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Mackintosh
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Petricoin
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20110, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhou
authors.affiliation: McClellan Veterans Medical Center, Central Arkansas Veterans Healthcare Service, Little Rock, AR, 72205, USA. rjsr@uams.edu.|Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. rjsr@uams.edu.|Department of Biochemistry & Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. rjsr@uams.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Shmookler Reis
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D016923:Cell Death / Q000187:drug effects; D003902:Detergents / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D040901:Proteomics; D012995:Solubility; D016875:tau Proteins / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D003902:Detergents; D007381:Intermediate Filament Proteins; C046643:alpha-internexin; D016875:tau Proteins
keywords: Abeta(1-42); Alzheimer (Disease); C. elegans; acetylation (protein); aggregation (protein); beta amyloid; microtubule-associated protein tau; neurodegeneration; neurotoxicity; oxidation (protein); phosphorylation (protein); proteomics