Cholinotoxicity of betta-amyloid

Many Alzheimer patients demonstrate also cerebral amyloid angiopathy and microvascular degeneration. The upregulation of the angiogenic vascular endothelial growth factor (VEGF) in brains of Alzheimer patients in close relationship to β-amyloid plaques, suggests a link of VEGF action and processing of the amyloid precursor protein (APP). As the brain vascular system underlies a functional control by basal forebrain cholinergic terminals, the question arises of whether there is a relationship between damage of brain capillaries, VEGF upregulation, and cortical cholinergic denervation. Tg2576 mice, that express the Swedish double mutation of human amyloid precursor protein and progressively develop β-amyloid deposits, were used to study age- and β-amyloid related changes in cerebral cortical microvessels, VEGF level, and associated cholinergic terminals. Treatment of brain slices with VEGF affected the formation of soluble β-amyloid, while the overproduction of β-amyloid led to signifi cant decrease of cholinergic fi bre density in cortical regions of aged transgenic mice. The data further suggest that changes in cholinergic innervation of microvessels may contribute to pathological alterations of the cerebrovascular system. Supported by IZKF, University Leipzig, and Alzheimer Forschungsinitiative (AFI)