Chronic overproduction of transforming growth factor-beta 1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice

Cerebrovascular amyloid deposition and microvascular degeneration are frequ ently associated with Alzheimer's disease (AD), but the etiology and pathog enetic role of these abnormalities are unknown, Recently, transforming grow th factor-beta 1 (TGF-beta 1) was implicated in cerebrovascular amyloid for mation in transgenic mice with astroglial overproduction of TGF-beta 1 and in AD. We tested whether TGF-beta 1 overproduction induces AD-like cerebrov ascular degeneration and analyzed how cerebrovascular abnormalities develop over time in TGF-beta 1-transgenic mice. In cerebral microvessels from 3- to 4-month-old TGF-beta 1-transgenic mice, which display a prominent periva scular astrocytosis, levels of the basement membrane proteins perlecan and fibronectin were severalfold higher than in vessels from nontransgenic mice . Consistent with this increase, cortical capillary basement membranes of T GF-beta 1 mice were significantly thickened, These changes preceded amyloid deposition, which began at around 6 months of age. In 9- and 18-month-old TGF-beta 1 mice, various degenerative changes in microvascular cells of the brain were observed. Endothelial cells were thinner and displayed abnormal , microvilli-like protrusions as well as occasional condensation of chromat in, and pericytes occupied smaller areas in capillary profiles than in nont ransgenic controls. Similar cerebrovascular abnormalities have been reporte d in AD. Wie conclude that chronic overproduction of TGF-beta 1 triggers an accumulation of basement mem brane proteins and results in AD-like cerebro vascular amyloidosis and microvascular degeneration. Closely related proces ses may induce cerebrovascular pathology in AD.