Reduction of the cerebrovascular volume in a transgenic mouse model of Alzheimer's disease

Combined evidence from neuroimaging and neuropathological studies shows that signs of vascular pathology and brain hypoperfusion develop early in Alzheimer's disease (AD). To investigate the functional implication of these abnormalities, we have studied the cerebrovascular volume and selected markers of blood-brain barrier (BBB) integrity in 11-month-old 3×Tg-AD mice, using the in situ brain perfusion technique. The cerebrovascular volume of distribution of two vascular space markers, [3H]-inulin and [14C]-sucrose, was significantly lower (−26% and −27%, respectively; p < 0.01) in the brain of 3×Tg-AD mice compared to non-transgenic littermates. The vascular volume reduction was significant in the hippocampus (p < 0.01), but not in the frontal cortex and cerebellum. However, the brain transport coefficient (Clup) of [14C]-d-glucose (1 μM) and [3H]-diazepam was similar between 3×Tg-AD mice and controls, suggesting no difference in the functional integrity of the BBB. We also report a 32% increase (p < 0.001) in the thickness of basement membranes surrounding cortical microvessels along with a 20% increase (p < 0.05) of brain collagen content in 3×Tg-AD mice compared to controls. The present data indicate that the cerebrovascular space is reduced in a mouse model of Aβ and tau accumulation, an observation consistent with the presence of cerebrovascular pathology in AD.