Cerebrovascular disease is a major factor in the failure of elimination of Abeta from the aging human brain: implications for therapy of Alzheimer's disease

Roy O Weller, Hong-Yeen Yow, Stephen D Preston, Ingrid Mazanti, James A R Nicoll
Annals of the New York Academy of Sciences 2002, 977: 162-8
Alzheimer's disease (AD) is characterized by the intracellular deposition of ubiquitinated tau and by the extracellular accumulation of soluble, insoluble, and fibrillary Abeta. Previous studies suggest that Abeta is normally eliminated from the brain along perivascular pathways that may become blocked in the aging brain, resulting in cerebral amyloid angiopathy. As age is a major risk factor for AD and for cerebrovascular disease (CVD), we test the hypothesis that CVD inhibits the elimination of Abeta from the aging human brain. Sections from 100 aged and AD brains were stained for Abeta by immunohistochemistry and by reticulin and Masson trichrome techniques. Early deposition of Abeta in brain parenchyma was related to individual arterial territories in the cortex. In areas of more extensive accumulation of Abeta, there was an inverse relationship between capillary amyloid angiopathy and plaques of Abeta. Thus, arterial territories with extensive capillary amyloid angiopathy were devoid of Abeta plaques, whereas in areas with abundant diffuse plaques there was no capillary amyloid angiopathy. Serial sections showed that cortical arteries feeding capillary beds with Abeta angiopathy were occluded by thrombus. We conclude that CVD inhibits the elimination of Abeta along capillary walls and changes the distribution of Abeta in the cerebral cortex. Loss of pulsations in thrombosed or arteriosclerotic arteries may thus abolish the motive force necessary for the drainage of Abeta and inhibit the elimination of Abeta. Therapies to increase elimination of Abeta in AD need to consider the effects of CVD on the elimination of Abeta from the aging human brain.

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