Amyloid-β 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.