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The Journal of Neuroscience, April 14, 2004, 24(15):3801-3809; doi:10.1523/JNEUROSCI.5543-03.2004
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Neurobiology of Disease
Dimeric Amyloid  Protein Rapidly Accumulates in Lipid Rafts followed by Apolipoprotein E and Phosphorylated Tau Accumulation in the Tg2576 Mouse Model of Alzheimer's Disease
Takeshi Kawarabayashi,1
Mikio Shoji,1
Linda H. Younkin,2
Lin Wen-Lang,2
Dennis W. Dickson,2
Tetsuro Murakami,1
Etsuro Matsubara,1
Koji Abe,1
Karen Hsiao Ashe,3 and
Steven G. Younkin2
1Department of Neurology, Okayama University Graduate School of Medicine, Okayama, 700-8558, Japan, 2Mayo Clinic Jacksonville, Jacksonville, Florida 32224, and 3Departments of Neurology and Neuroscience, University of Minnesota, and Minneapolis Veterans Affairs Hospital, Minneapolis, Minnesota 55455
To investigate lipid rafts as a site where amyloid  protein (A) oligomers might accumulate and cause toxicity in Alzheimer's disease (AD), we analyzed A in the Tg2576 transgenic mouse model of AD. A was highly concentrated in lipid rafts, which comprise a small fraction of brain volume but contain 27% of brain A42 and 24% of A40 in young mice. In the Tg2576 model, memory impairment begins at 6 months before amyloid plaques are visible. Here we show that A dimers appear in lipid rafts at 6 months and that raft A, which is primarily dimeric, rapidly accumulates reaching levels >500x those in young mice by 24–28 months. A similar large accumulation of dimeric A was observed in lipid rafts from AD brain. In contrast to extracellular amyloid fibrils, which are SDS-insoluble, virtually all A in lipid rafts is SDS soluble. Coupled with recent studies showing that synthetic and naturally occurring A oligomers can inhibit hippocampal long-term potentiation, the in vivo age-dependent accumulation of SDS-soluble A dimers in lipid rafts at the time when memory impairment begins in Tg2576 mice provides strong evidence linking A oligomers to memory impairment. After dimeric A began to accumulate in lipid rafts of the Tg2576 brain, apolipoprotein E (ApoE) and then phosphorylated tau accumulated. A similar increase in ApoE and a large increase in phosphorylated tau was observed in lipid rafts from AD brain. These findings suggest that lipid rafts may be an important site for interaction between dimeric A, ApoE, and tau.
Key words: lipid rafts; amyloid protein; Alzheimer's disease; ApoE; tau; Tg2576 mouse model
Received Dec 16, 2003;
revised February 9, 2004;
accepted February 9, 2004.
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