Amyloid-o protofibril levels correlate with spatial learning in Arctic Alzheimer's disease transgenic mice

摘要

Oligomeric assemblies of amyloid-o (Ao) are suggested to be central in the pathogenesis of Alzheimer's disease because levels of soluble Ao correlate much better with the extent of cognitive dysfunctions than do senile plaque counts. Moreover, suchAo species have been shown to be neurotoxic, to interfere with learned behavior and to inhibit the maintenance of hippocampal long-term potentiation. The tg-ArcSwe model (i.e. transgenic mice with the Arctic and Swedish Alzheimer mutations) expresses elevated levels of Ao protofibrils in the brain, making tg-ArcSwe a highly suitable model for investigating the pathogenic role of these Ao assemblies. In the present study, we estimated Ao protofibril levels in the brain and cerebrospinal fluid of tg-ArcSwe mice, and also assessed their role with respect to cognitive functions. Protofibril levels, specifically measured with a sandwich ELISA, were found to be elevated in young tg-ArcSwe mice compared to several transgenic models lacking the Arctic mutation. In aged tg-ArcSwe mice with considerable plaque deposition, Ao protofibrils were approximately 50% higher than in younger mice, whereas levels of total Ao were exponentially increased. Young tg-ArcSwe mice showed deficits in spatial learning, and individual performances in the Morris water maze were correlated inversely with levels of Ao protofibrils, but not with total Ao levels. We conclude that Ao protofibrils accumulate in an age-dependent manner in tg-ArcSwe mice, although to a far lesser extentthan total Ao. Our findings suggest that increased levels of Ao protofibrils could result in spatial learning impairment.