title: Proteomic determination of widespread detergent-insolubility including Abeta but not tau early in the pathogenesis of Alzheimer's disease.
abstract: Biochemical characterization of the major detergent-insoluble proteins that comprise hallmark histopathologic lesions initiated the molecular era of Alzheimer's disease (AD) research. Here, we reinvestigated detergent-insoluble proteins in AD using modern proteomic techniques. Using liquid chromatography (LC)-mass spectrometry (MS)-MS-based proteomics, we robustly identified 125 proteins in the detergent-insoluble fraction of late-onset AD (LOAD) temporal cortex that included several proteins critical to Abeta production, components of synaptic scaffolding, and products of genes linked to an increased risk of LOAD; we verified 15 of 15 of these proteins by Western blot. Following multiple analyses, we estimated that these represent ~80% of detergent-insoluble proteins in LOAD detectable by our method. Abeta, tau, and 7 of 8 other newly identified detergent-insoluble proteins were disproportionately increased in temporal cortex from patients with LOAD and AD derived from mutations in PSEN1 and PSEN2; all of these except tau were elevated in individuals with prodromal dementia, while none except Abeta were elevated in aged APPswe mice. These results are consistent with the amyloid hypothesis of AD and extend it to include widespread protein insolubility, not exclusively Abeta insolubility, early in AD pathogenesis even before the onset of clinical dementia.
authors.affiliation: Department of Pathology, Division of Neuropathology, University of Washington, Seattle, WA, USA.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Woltjer
authors.forename: P J
authors.initials: PJ
authors.lastname: Cimino
authors.forename: Angela M
authors.initials: AM
authors.lastname: Boutté
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Schantz
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.forename: Thomas
authors.initials: T
authors.lastname: Bird
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000682:Amyloid / Q000737:chemistry; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002853:Chromatography, Liquid; D003704:Dementia / Q000473:pathology; D003713:Dendritic Cells / Q000378:metabolism; D003902:Detergents / Q000378:metabolism / Q000494:pharmacology*; D018450:Disease Progression; D005799:Genes, Dominant; D006801:Humans; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D011485:Protein Binding; D025941:Protein Interaction Mapping; D040901:Proteomics / Q000379:methods*; D016875:tau Proteins / Q000737:chemistry*
chemical_list: D000682:Amyloid; D003902:Detergents; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D016875:tau Proteins