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 ␤ 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 A␤42 and 24% of A␤40 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 Ͼ500ϫ 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.

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

“…38 In other experiments using APP transgenic mice, the onset of cognitive deficits was found to coincide with the formation of dimeric Ab within cortical lipid rafts. 39 Therefore it is difficult to ascribe neurotoxicity to a particular Ab species. However, as described in the following sections of this review, a number of Ab-binding molecules can alter the rate of Ab fibril formation, thus potentiating or preventing these toxic intermediate species as well as influencing Ab deposition.…”

Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway

“…AD (Kawarabayashi et al, 2004). Lastly, these oligomers have been shown to alter LTP and memory performance directly on their secretion from cells, requiring no in vitro manipulation of the conditioned media (Walsh et al, 2002;Cleary et al, 2005).…”

Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior

“…[47,67]. Dimeric, trimeric and apparently tetrameric soluble oligomers have been described in cultured cells [47,67], and SDS-stable oligomers of varying sizes have also been detected by Western blotting in APP transgenic mouse brain and human brain [14,16,27,33,40,49]. Such natural (i.e., non-synthetic) Aβ oligomers can be resistant not only to SDS but also to chaotropic salts like guanidine hydrochloride and to the Aβ-degrading protease IDE (insulin-degrading enzyme), which can only efficiently digest monomeric Aβ [65].…”