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Keywords:

  • Alzheimer's disease (AD);
  • TGF-β1;
  • β-amyloid (Aβ);
  • cerebral amyloid angiopathy;
  • cerebrovascular abnormalities;
  • hemorrhage;
  • transgenic

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-β1 (TGF-β1) 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-β1 in human cerebrovascular abnormalities. Transgenic mice overexpressing TGF-β1 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-β1 alone or in addition to human amyloid precursor protein (hAPP) show selective accumulation of human β-amyloid (Aβ) in blood vessels and develop cerebral hemorrhages in old age. In 9-month-old TGF-β1 transgenic mice, cerebral blood flow (CBF) in the limbic system was significantly less than in nontransgenic littermate controls. Aged TGF-β1 mice also showed overall reduced cerebral glucose uptake (CGU) as a measure of brain activity. Thus, chronic overproduction of TGF-β1 in the brain results in structural and functional impairments reminiscent of those in AD cases with amyloid angiopathy.