Amyloid-β contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-β (Aβ) deposition in the blood-brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to Aβ compromising the BBB. METHODS We characterized 19 patients with acute stroke with "probable CAA" for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of Aβ on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels. RESULTS Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. Aβ(40) decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls. CONCLUSIONS Our findings indicate that Aβ contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that Aβ causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.