Therapeutic and functional studies in animal models of Alzheimer's disease

Abstract: Senile plaques (A?) and neurofibrillary tangles (tau) are pathological hallmarks of Alzheimer’s disease (AD). If and how the formation of these deposits are mechanistically linked remains mainly unknown. In recent years, the focus has shifted from insoluble protein deposits to soluble aggregates of A? and tau. Protofibrils are large soluble A? oligomers which were linked to AD by the discovery of the Arctic A?PP mutation.Treatment of young tg-ArcSwe mice with an A? protofibril-selective antibody, mAb158, cleared protofibrils, prevented amyloid plaque deposition and protected cultured cells from protofibril-mediated toxicity. This suggests that A? protofibrils are necessary for the formation of A? deposits. Functional assessment of tg-ArcSwe mice in IntelliCage demonstrated hippocampal-dependent behavioral deficits such as memory/learning impairments, hyperactivity and perseverance behavior. Learning impairments did not correlate to A?-measures but to calbindin, which might be a good marker for A?-mediated neuronal dysfunction.Splicing of exon 10 in the tau gene differs between human and mouse brain. Exon 10 is part of the microtubule-binding domains which helps to maintain microtubule stability and axonal transport, functions vital to neuronal viability. Axonal transport dysfunction has been proposed as a common pathway of A? and tau pathogenesis in AD. Generation of a novel tau mouse model with absence of exon 10 led to age-dependent sensorimotor impairments which may relate to dysfunctions in cerebellum. No tau pathology was evident suggesting that a trigger of tau fibrillization e.g. a human A? or tau aggregate is needed. Generation of A?PPxE10 bitransgenic mice with no exon 10 showed lower A? plaque burden. Possibly changes in microtubule function lead to altered intracellular A?PP transport and A? production. Initiation of tau pathology in A?PPxE10 mice might require a certain type of A?-aggregates which is not produced or exist at too low concentration in transgenic mouse brain.In summary, the A? protofibril-selective antibody was found to be a promising treatment for AD. The IntelliCage system was proven to be useful for functional evaluation of A?PP mice. Exon 10 in tau was shown to affect sensorimotor functions and A? pathology in bitransgenic mice by mechanisms that deserve further investigation.