A specific amyloid-beta protein assembly in the brain impairs memory.
Memory function often declines with age, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-beta precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-beta protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6-14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-beta (refs 3-6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-beta assembly, which we term Abeta*56 (Abeta star 56). Abeta*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.
Lesné
Sylvain
S
Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
Koh
Ming Teng
MT
Kotilinek
Linda
L
Kayed
Rakez
R
Glabe
Charles G
CG
Yang
Austin
A
Gallagher
Michela
M
Ashe
Karen H
KH
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008970:Molecular Weight; D058225:Plaque, Amyloid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020836:Protein Structure, Quaternary; D051381:Rats; D012995:Solubility; D013997:Time Factors
D016229:Amyloid beta-Peptides