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Dimeric Amyloid β Protein Rapidly Accumulates in Lipid Rafts followed by Apolipoprotein E and Phosphorylated Tau Accumulation in the Tg2576 Mouse Model of Alzheimer's Disease
Abstract
To investigate lipid rafts as a site where amyloid β protein (Aβ) oligomers might accumulate and cause toxicity in Alzheimer's disease (AD), we analyzed Aβ in the Tg2576 transgenic mouse model of AD. Aβ was highly concentrated in lipid rafts, which comprise a small fraction of brain volume but contain 27% of brain Aβ42 and 24% of Aβ40 in young mice. In the Tg2576 model, memory impairment begins at 6 months before amyloid plaques are visible. Here we show that Aβ dimers appear in lipid rafts at 6 months and that raft Aβ, which is primarily dimeric, rapidly accumulates reaching levels >500× those in young mice by 24–28 months. A similar large accumulation of dimeric Aβ was observed in lipid rafts from AD brain. In contrast to extracellular amyloid fibrils, which are SDS-insoluble, virtually all Aβ in lipid rafts is SDS soluble. Coupled with recent studies showing that synthetic and naturally occurring Aβ oligomers can inhibit hippocampal long-term potentiation, the in vivo age-dependent accumulation of SDS-soluble Aβ dimers in lipid rafts at the time when memory impairment begins in Tg2576 mice provides strong evidence linking Aβ oligomers to memory impairment. After dimeric Aβ 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 Aβ, ApoE, and tau.
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“This is in good accordance with a recent article showing that ApoE, a LRP ligand, is co-localized with APP and BACE in lipid rafts (46).”
From The Low Density Lipoprotein Receptor-related Protein (LRP) Is a Novel β-Secretase (BACE1) Substrate (2005) · cites this paper as [46]
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Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
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Metadata
- Authors
- Kawarabayashi, T., Shoji, M., Younkin, L. H., Wen-Lang, L., Dickson, D. W., Murakami, T., Matsubara, E., Abe, K., Ashe, K. H., & Younkin, S. G.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-04-14
- Volume
- 24
- Issue
- 15
- Pages
- 3801-3809
- ISSN
- 0270-6474
- 1529-2401
- Cited by
- 320
- References
- 11
- Language
- en
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