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Abstract
Cerebrovascular abnormalities, such as reduced blood flow, microvascular fibrosis, and cerebrovascular amyloid angiopathy, are prominent in Alzheimer's disease (AD). However, their etiology is poorly understood and it is unclear whether cerebrovascular changes contribute to functional impairments in the absence of neurodegeneration. In humans with AD, transforming growth factor-beta1 (TGF-beta1) mRNA levels in the midfrontal gyrus correlate positively with the relative degree of cerebrovascular amyloid deposition in that brain region, suggesting a possible role for TGF-beta1 in human cerebrovascular abnormalities. Transgenic mice overexpressing TGF-beta1 in astrocytes develop AD-like cerebrovascular abnormalities, including perivascular astrocytosis, microvascular basement membrane thickening, and accumulation of thioflavin S-positive amyloid in the absence of parenchymal degeneration. Mice overexpressing TGF-beta1 alone or in addition to human amyloid precursor protein (hAPP) show selective accumulation of human beta-amyloid (Abeta) in blood vessels and develop cerebral hemorrhages in old age. In 9-month-old TGF-beta1 transgenic mice, cerebral blood flow (CBF) in the limbic system was significantly less than in nontransgenic littermate controls. Aged TGF-beta1 mice also showed overall reduced cerebral glucose uptake (CGU) as a measure of brain activity. Thus, chronic overproduction of TGF-beta1 in the brain results in structural and functional impairments reminiscent of those in AD cases with amyloid angiopathy.
View details for Web of Science ID 000179767000009
View details for PubMedID 12480736