Senile plaques in Alzheimer's disease arise from A beta- and Cathepsin D-enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture

Senile plaques are a pathological hallmark of Alzheimer's disease (AD), yet the mechanism underlying their generation remains unknown. Beta-amyloid peptide (A beta) is a major component of senile plaques. We analysed AD brain tissues with histochemistry, immunohistochemistry and fluorescence imaging to examine the neural, vascular or blood A beta contribution to senile plaque development. We found little neural marker co-expression with plaque A beta, while co-expression of blood markers, such as Haemin and ApoE, was abundant. The plaque cores were structured with vascular and glial proteins outside and blood metabolites inside, co-localizing with a characteristic of Hoechst staining-independent blue autofluorescence. Erythrocyte-interacting A beta is linked to coagulation, elevated calcium and blue autofluorescence, and it is associated with intravascular haemolysis, atherosclerosis, cerebral amyloid angiopathy, microaneurysm, and often with Cathepsin D co-expression. We identified microaneurysms as major sites of amyloid formation. Our data suggest that senile plaques arise from A beta- and Cathepsin D-enriched mixtures leaking out during intravascular haemolysis and microaneurysm rupture.