Quantitation and mapping of cerebral detergent-insoluble proteins in the elderly.
Accumulation of abnormal protein aggregates, detergent-insoluble (DI) proteins and amyloid in the brain are shared features of many neurodegenerative diseases. Previous studies correlating DI proteins and cognitive performance are limited. We addressed these limitations using two sets of autopsy brains, one selected from our Alzheimer's Disease Research Center and the other an unselected series from Adult Changes in Thought (ACT), a population-based study of brain aging. We observed concentrations of 11 proteins and 6 protein variants that can be grouped into three highly correlated clusters: amyloid (A)beta, tau and alpha-synuclein (alpha-syn). While abnormal proteins from each cluster independently correlated with cognitive performance in ACT participants, only increased soluble Abeta oligomers in temporal cortex and increased DI Abeta 42 and DI alpha-syn in prefrontal cortex were negatively correlated with cognitive performance. These data underscore the therapeutic imperative to suppress processes leading to accumulation of soluble Abeta oligomers, DI Abeta 42 and DI alpha-syn, highlight an at least partially independent contribution to cognitive impairment and raise the possibility that the priority for therapeutic targets may vary by brain region in a typical elderly US population.
Woltjer
Randall L
RL
Department of Pathology Oregon Health Sciences University, Portland, OR 97239-3098, USA. woltjerr@ohsu.edu
Sonnen
Joshua A
JA
Sokal
Izabela
I
Rung
Lisa G
LG
Yang
Wan
W
Kjerulf
John D
JD
Klingert
Danielle
D
Johnson
Charles
C
Rhew
Isaac
I
Tsuang
Debbie
D
Crane
Paul K
PK
Larson
Eric B
EB
Montine
Thomas J
TJ
D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001921:Brain / Q000473:pathology*; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D051844:alpha-Synuclein; D016875:tau Proteins