Address for correspondence: Tony Wyss-Coray, Ph.D., Department of Neurology and Neurological Sciences, SUMC, Room A-343, Stanford, CA 94305. Voice: 650-852-3220; fax: 650-858-3999.
twc{at}stanford.edu
Ann. N.Y. Acad. Sci. 977: 87-95 (2002).
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-ß1 (TGF-ß1)
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-ß1
in human cerebrovascular abnormalities. Transgenic mice overexpressing
TGF-ß1 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-ß1 alone or in addition to
human amyloid precursor protein (hAPP) show selective accumulation
of human ß-amyloid (Aß) in blood vessels
and develop cerebral hemorrhages in old age. In 9-month-old
TGF-ß1 transgenic mice, cerebral blood flow (CBF)
in the limbic system was significantly less than in nontransgenic
littermate controls. Aged TGF-ß1 mice also showed
overall reduced cerebral glucose uptake (CGU) as a measure of
brain activity. Thus, chronic overproduction of TGF-ß1
in the brain results in structural and functional impairments
reminiscent of those in AD cases with amyloid angiopathy.
