LI LIU Cholinergic Neurotransmission , Amyloid-β Peptide and the Pathogenesis of Alzheimer ’ s Disease A study in the APP and PS 1 double transgenic mouse model

Alzheimer’s disease (AD) is characterized clinically by a progressive decline in cognition, and histopathologically by the presence of senile plaques (consisting mainly of amyloid-β, Aβ) and neurofibrillary tangles in the brain, and the degeneration of basal forebrain cholinergic neurons. Aβ, a 39-43 amino acid long peptide, is derived by proteolytic processing from its precursor, the amyloid precursor protein (APP). Growing evidence indicates that the accumulation and deposition of Aβ in the brain, which may result from overproducion due to APP mismetabolism, or/and a failure in the clearance, is central to the pathogenesis of AD. In recent years, a number of in vitro and in vivo studies have suggested that cholinergic neurotransmission may be involved in the regulation of APP metabolism. However, the two questions raised by these findings, i.e. whether cholinergic dysfunction would lead to an increased Aβ production and thus deposition of Aβ in AD brain, and whether this process could be prevented by restoring or enhancing cholinergic activity, have not yet been studied in an in vivo model of AD. In addition, the question regarding the pivotal role of Aβ overproduction and/or deposition in the development of cognitive impairments in AD needs to be further addressed in a suitable disease model. In the present study we used APPswe and PS1(A246E) double transgenic mice (AP mice) as an AD model. These mice develop the first amyloid deposits around the age of 9 months and age-related cognitive deficits at a later age. In these mice, we manipulated the level of acetylcholine (ACh) by two methods, 1) by treatment with a cholinesterase inhibitor, metrifonate, to increase the level of ACh, or 2) by fimbria-fornix lesion, to lower the ACh level in the hippocampus, in order to investigate the consequences of these changes on APP metabolism and Aβ deposition. In addition, we investigated the relation between the cognitive deficits and Aβ overproduction and/or deposition in these mice. We demonstrated that neither an increase nor a reduction in the level of ACh significantly affected APP metabolism, Aβ production and the deposition of Aβ. Our results do not support the idea that cholinergic dysfunction would promote the process of Aβ production and deposition, or that an enhancement in cholinergic activity would slow down the progression of amyloid pathology in AD; conversely they indicate that APP metabolism may not be regulated by the level of ACh, at least in the AP mice that were used in our studies. In the AP mice, the early amyloid deposits are largely restricted to the dorsal hippocampal formation; accordingly the mice showed a selective impairment in hippocampal-dependent long-term spatial memory. Furthermore, the impaired memory significantly correlated with the amount of insoluble Αβ42, but not that of soluble Αβ42 in the hippocampus, or the Aβ levels in the CSF and serum. Together, these findings support the role of insoluble Αβ42 in the development of memory impairments in AD. National Library of Medicine Classification: WL 359, QV 126 Medical Subject Headings: Alzheimer disease/pathology; amyloid beta-protein precursor/ metabolism; amyloid-beta protein; brain/drug effect/pathology; hippocampus /pathology /physiology; acetylcholine; cholinesterase inhibitors/therapeutic use; memory; cognition; maze learning; disease models, animal; mice, transgenic