Glial reactions and the clearance of amyloid [beta] protein in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type

Although the amyloid [beta] protein (A[beta]) E693Q mutation enhances A[beta] fibrillization in vitro and cerebral amyloid angiopathy (CAA) in vivo, brain parenchymal A[beta] deposition and tau pathology in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) are limited. To evaluate whether clearance of A[beta] by glial cells may play a role in this regard, this immunohistochemical study of frontal cortex of 14 HCHWA-D autopsy brains was performed using double staining with glial markers and end-specific antibodies to A[beta]x-42 (A[beta]42) and A[beta]x-40 (A[beta]40). Tau pathology was also assessed. Numerous microglia and/or astrocytes carrying cytoplasmic A[beta]42+40- granules were scattered among non-fibrillar (Congo red-negative) A[beta] deposits, i.e., clouds, fine diffuse plaques, and A[beta]42+40- dense diffuse plaques. On the other hand, activated microglia and reactive astrocytes associated with fibrillar (Congo red-positive) A[beta] deposition, i.e., A[beta]42+40+ dense diffuse plaques and CAA invading the parenchyma, were virtually devoid of A[beta] granules. Tau pathology was scant and most frequently associated with CAA. These results suggest that relatively non-fibrillar parenchymal A[beta] deposits may be liable to glial clearance. A[beta] sequestration by glial cells may be a factor limiting the levels of neurotoxic soluble A[beta] oligomers in HCHWA-D brain.