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Proteomic determination of widespread detergent insolubility, including Aβ but not tau, early in the pathogenesis of Alzheimer's disease
Author(s) -
Woltjer Randall L.,
Cimino P. J.,
Boutté Angela M.,
Schantz Aimee M.,
Montine Kathleen S.,
Larson Eric B.,
Bird Thomas,
Quinn Joseph F.,
Zhang Jing,
Montine Thomas J.
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-4263fje
Subject(s) - pathogenesis , proteomics , alzheimer's disease , western blot , dementia , disease , tau protein , psen1 , chemistry , biochemistry , biology , presenilin , neuroscience , medicine , pathology , gene
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 Aβ 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. Aβ, 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 Aβ 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 Aβ insolubility, early in AD pathogenesis even before the onset of clinical dementia.