Abstract
Alzheimer's disease is characterized by two major morpho–pathological hallmarks, β–amyloid peptide–containing plaques and neurofibrillary tangles. A consistent feature of Alzheimer's disease is the loss of basal forebrain cholinergic neurons, which has been assumed to cause the cognitive impairments observed in Alzheimer's patients. The present work addresses the hypothesis that amyloid precursor protein (APP) metabolism underlies a basal forebrain cholinergic control. To study interactions between APP processing, cholinergic activity and cognitive function, transgenic Tg2576 mice (7–9 months of age) subjected to partial basal forebrain cholinergic lesion were used. Lesioning was carried out by stereotaxic i.c.v. microinjection of 2 μl (1 μg) of the cholinergic immunotoxin mu p75–saporin. Two weeks following lesion, mice were subjected to behavioral tests, and subsequently brains were examined for acetylcholinesterase (AChE) histochemistry and beta–amyloid levels by ELISA. Analysis of AChE activity in hippocampus of lesioned mice revealed significant decreases by 68% in wild–type (WT) and by 88% in transgenic mice. In the cortex, only transgenic lesioned mice showed significant reductions in AChE activity (39%). Transgenic mice, regardless of the lesion, showed important spatial memory impairments in the Morris water maze, while lesioned WT mice showed partial learning deficits. The novel object recognition test revealed in lesioned mice, both WT and transgenic, significant cognitive deficits. β–amyloid (Aβ)1–40 and Aβ1–42 levels were found to be increased with age in transgenic mice. These increases were significantly higher in cholinergically lesioned transgenic animals (soluble Aβ1–40 by 60%; fibrillar Aβ1–40 by 73%; soluble Aβ1–42 by 14–fold; fibrillar Aβ1–42 by 2.3–fold). Levels of Aβ1–40 (soluble and fibrillar) were correlated to retention time in the Morris water maze in transgenic mice, but this correlation was lost in the lesioned group. Cholinergic neurons of Tg2576 mice appear to be especially vulnerable to a cholinergic lesion. Basal forebrain cholinergic dysfunction favours the amyloidogenic route of APP processing in Tg2576 mice by increasing Aβ species, which does not lead to further cognitive impairments.
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