Aβ reduction at early disease stages prevents progression of cerebral amyloid angiopathy in a mouse model ofhereditary cerebral hemorrhage with amyloidosis - Dutch type

Introduction: Deposition of -amyloid peptide (A) within cerebral vessels (cerebral amyloid angiopathy, CAA) contributes to intracerebral bleedings and altered brain function. CAA occurs with aging and to various degree in Alzheimer’s disease. Methods: APPDutch mice model hereditary cerebral hemorrhage with amyloidosis – Dutch-type (HCHWA-D) and develop CAA in the vast absence of parenchymal amyloid. 3D-ultramicroscopy and immunoassays were used to assess CAA onset and progression. An inhibitor to the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) was used to lower A generation. Results: CAA was first detected in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. Upon CAA onset, A in the CSF was decreased. BACE1-inhibition initiated at the onset of CAA, and continued for 4 months, largely prevented CAA progression and associated microgliosis. Discussion: Results provide a preclinical basis for A-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D mutation carriers.