Alzheimer's Disease-like Cerebrovascular Pathology in Transforming Growth Factor-?1 Transgenic Mice and Functional Metabolic Correlates

Alzheimer's disease (AD) is frequently associated with cerebrovascular changes, including perivascular astrocytosis, amyloid deposition, and microvascular degeneration, but it is not known whether these pathological changes contribute to functional deficits in AD. To characterize the temporal relationship between amyloid deposition, cerebrovascular abnormalities, and potential functional changes, we studied transgenic mice that express transforming growth factor-?1 (TGF-?1) at low levels in astrocytes. TGF-?1 induced a prominent perivascular astrocytosis, followed by the accumulation of basement membrane proteins in microvessels, thickening of capillary basement membranes, and later, around 6 months of age, deposition of amyloid in cerebral blood vessels. At 9 months of age, various AD-like degenerative alterations were observed in endothelial cells and pericytes. Associated with these morphological changes were changes in regional cerebral glucose utilization. Preliminary results showed that TGF-?1 mice had significantly decreased glucose utilization in the mammillary bodies, structures involved in mnemonic and learning processes. Glucose utilization tended to be decreased in several other brain regions as well; however, in the inferior colliculus, it was markedly higher in TGF-?1 mice than in controls. We conclude that chronic overproduction of TGF-?1 triggers a pathogenic cascade leading to AD-like cerebrovascular amyloidosis, microvascular degeneration, and local alterations in brain metabolic activity. Similar mechanisms may be involved in AD pathogenesis.