Amyloid beta-protein induces the cerebrovascular cellular pathology of Alzheimer's disease and related disorders

Abstract

One of the hallmark pathologic characteristics of Alzheimer's disease (AD) and related disorders is deposition of the 39-42 amino acid amyloid beta-protein (A beta) in the walls of cerebral blood vessels. The cerebrovascular A beta deposits in these disorders are associated with degenerating smooth muscle cells in the vessel wall which have been implicated in the expression of the amyloid beta-protein precursor (A beta PP) and formation of A beta. We have established primary cultures of human cerebrovascular smooth muscle cells as a model for investigating the cellular pathologic processes involved in the cerebral amyloid angiopathy of AD and related disorders. Recently, we have shown that A beta 1-42, the predominant pathologic cerebrovascular form of A beta, causes extensive cellular degeneration that is accompanied by a striking increase in the levels of cellular A beta PP, potentially amyloidogenic carboxyl terminal A beta PP fragments, and soluble A beta peptide in the cultured human cerebrovascular smooth muscle cells. Together, these studies provide evidence that A beta contributes to the onset and progression of the cerebrovascular pathology associated with AD and related disorders and suggests the mechanism involves a molecular cascade with a novel product-precursor relationship that results in the adverse production and accumulation of A beta.