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

Although the amyloid β protein (Aβ) E693Q mutation enhances Aβ fibrillization in vitro and cerebral amyloid angiopathy (CAA) in vivo, brain parenchymal Aβ deposition and tau pathology in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) are limited. To evaluate whether clearance of Aβ 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 Aβx–42 (Aβ42) and Aβx–40 (Aβ40). Tau pathology was also assessed. Numerous microglia and/or astrocytes carrying cytoplasmic Aβ42+40− granules were scattered among non-fibrillar (Congo red-negative) Aβ deposits, i.e., clouds, fine diffuse plaques, and Aβ42+40− dense diffuse plaques. On the other hand, activated microglia and reactive astrocytes associated with fibrillar (Congo red-positive) Aβ deposition, i.e., Aβ42+40+ dense diffuse plaques and CAA invading the parenchyma, were virtually devoid of Aβ granules. Tau pathology was scant and most frequently associated with CAA. These results suggest that relatively non-fibrillar parenchymal Aβ deposits may be liable to glial clearance. Aβ sequestration by glial cells may be a factor limiting the levels of neurotoxic soluble Aβ oligomers in HCHWA-D brain.