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

Oligomeric assemblies of amyloid-[beta] (A[beta]) are suggested to be central in the pathogenesis of Alzheimer's disease because levels of soluble A[beta] correlate much better with the extent of cognitive dysfunctions than do senile plaque counts. Moreover, such A[beta] 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 A[beta] protofibrils in the brain, making tg-ArcSwe a highly suitable model for investigating the pathogenic role of these A[beta] assemblies. In the present study, we estimated A[beta] 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, A[beta] protofibrils were approximately 50% higher than in younger mice, whereas levels of total A[beta] 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 A[beta] protofibrils, but not with total A[beta] levels. We conclude that A[beta] protofibrils accumulate in an age-dependent manner in tg-ArcSwe mice, although to a far lesser extent than total A[beta]. Our findings suggest that increased levels of A[beta] protofibrils could result in spatial learning impairment. [PUBLICATION ABSTRACT]