Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function.
A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-beta protein interferes with cognitive function. Soluble oligomeric forms of amyloid-beta, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although beta-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-beta moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.
Cleary
James P
JP
Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota 55417, USA.
Walsh
Dominic M
DM
Hofmeister
Jacki J
JJ
Shankar
Ganesh M
GM
Kuskowski
Michael A
MA
Selkoe
Dennis J
DJ
Ashe
Karen H
KH
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D003072:Cognition Disorders / Q000139:chemically induced*; D003216:Conditioning, Operant / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D017077:Culture Media, Conditioned