Do solitary Aβ peptides begin their journey toward insoluble plaques by meeting up with partners on lipid rafts in the plasma membrane? Steve Younkin and colleagues report evidence that, in an APP-transgenic mouse model, Aβ dimerizes in the rafts and, what's more, that the rafts also accumulate ApoE and phosphorylated tau.
Lipid rafts have been gaining attention recently, as researchers have reported that many of the critical players in Aβ processing—Aβ40 and 42, presenilin 1, BACE, APP, and the C-terminal fragment from BACE cleavage—appear to catch rides on the rafts (see ARF related news story; Lee et al., 1998).
Working in the Tg2576 mouse model of Alzheimer's disease, first author Takeshi Kawarabayashi and colleagues from Okayama University in Japan, the Mayo Clinic in Jacksonville, Florida, and the University of Minnesota in Minneapolis report in the April 14 Journal of Neuroscience that they first confirmed previous findings that place the aforementioned Aβ acquaintances on the rafts. They also add evidence that the Aβ-degrading enzyme neprilysin is found in the rafts.
In the Tg2576 mouse, memory impairments are reported to appear at six months of age and aggregates of insoluble Aβ at six to eight months, with plaque deposition following soon after. The authors found that Aβ dimers appear in the rafts by six months of age, and that by old age (24-28 months) the levels have multiplied some 500 times. When they looked at human AD brain tissue, the authors similarly found high levels of Aβ in rafts relative to control brain.
Following on the heels of Aβ oligomerization, the authors identified progressive raft accumulations of ApoE beginning at 12 months of age, and phosphorylated tau beginning at 18 months of age. None of the other proteins examined—flotillin, APP, or APP CTF, or total tau—showed similar increases. The authors also found evidence of increases in ApoE and tau in human AD brain tissue.
The authors suggest that the results support a tidy model whereby the seeds of insoluble amyloid are sown in the lipid rafts. Because the rafts are on the outer edge of the cell membrane, it would theoretically be easy for these alleged Aβ oligomer rafters to be secreted and continue aggregating in the extracellular space. Further, write authors, "because lipid rafts play an important role in signal transduction and other cellular functions, the Aβ accumulating in lipid rafts is well-positioned to impair neuronal function in a way that could account for the memory loss observed in the Tg2576 model of AD."—Hakon Heimer
- Lee SJ, Liyanage U, Bickel PE, Xia W, Lansbury PT, Kosik KS. A detergent-insoluble membrane compartment contains A beta in vivo. Nat Med. 1998 Jun;4(6):730-4. PubMed.
- Kawarabayashi T, Shoji M, Younkin LH, Wen-Lang L, Dickson DW, Murakami T, Matsubara E, Abe K, Ashe KH, Younkin SG. Dimeric amyloid beta protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease. J Neurosci. 2004 Apr 14;24(15):3801-9. PubMed.