We have studied the functional repercussions of cerebrovascular abnormalities in transgenic mice overexpressing TGF-β1. These mice develop Alzheimer's disease-like vascular and meningeal alterations without parenchymal degeneration. Autoradiographic cerebral blood flow measurements in 9-month-old TGF-β1 mice compared to nontransgenic littermates provided evidence of reduced tissue perfusion, most prominent in limbic regions. A highly significant inverse correlation was found between the density of thioflavin-S-positive blood vessels and blood flow in the hippocampus and the cortex. An inverse correlation was likewise found between meningeal staining and blood flow in thalamic nuclei and regions of high blood flow. Thus, the vascular abnormalities were associated locally with reduced perfusion rate and more widely with limitation in the blood flow. These chronic changes may be related to fibrillar and soluble Aβ peptides, the amount of which was almost doubled in the brains of TGF-β1 mice. Comparison with previous results of cerebral glucose utilization in TGF-β1 mice shows that reduced utilization preferentially occurred in regions with a high metabolic rate and a relatively low blood flow, suggesting that the metabolic needs are not met by blood supply in these regions.
Bibliographical noteFunding Information:
This work was supported by grants from the CNRS UPR 646, the Université Paris 7, the IFR-6 Circulation-Lariboisière, and by the National Institutes of Health, grants AG15871 (T.W-C). The authors thank Elena Galea for complementary immunohistochemical investigations, Fred Checler for generously providing Aβ antibodies, and Vincent Brossard for expert contribution in data treatment and illustrations.
- Cerebral amyloid angiopathy
- Cerebral blood flow
- Cerebral glucose utilization
- TGF-β1 transgenic mice