Senile plaques in Alzheimer's disease arise from Aβ- and Cathepsin D-enriched mixtures leaking out during intravascular hemolysis 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 (Aβ) is a major component of senile plaques. We analyzed AD brain tissues with histochemistry, immunohistochemistry and fluorescence imaging to examine the neural, vascular or blood Aβ contribution to senile plaque development. We found little neural marker co-expression with plaque Aβ, while co-expression of blood markers, such as Hemin and ApoE, was abundant. The plaque cores were structured with vascular and glial proteins outside and blood metabolites inside, co-localizing with a characteristic Hoechst staining-independent blue autofluorescence. Erythrocyte-interacting Aβ is linked to coagulation, elevated calcium and blue autofluorescence, and it is associated with intravascular hemolysis, 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 Aβ- and Cathepsin D-enriched mixtures leaking out during intravascular hemolysis and microaneurysm rupture.