Abstract
Essentials Evidence suggests a comorbidity between hyperhomocysteinemia (HHC) and Alzheimer's disease (AD). Homocysteine (HC) could affect the β-amyloid (Aβ)-fibrinogen interaction in AD pathology. AD patients with concomitant HHC have increased fibrin and Aβ deposits in their brains. HC contributes to AD pathology via the Aβ-fibrinogen interaction. SUMMARY: Background Accumulating clinical evidence suggests that hyperhomocysteinemia (HHC) is correlated with Alzheimer's disease (AD) and vascular dementia. Objective This study was carried out to elucidate the specific role of elevated homocysteine (HC) levels in AD pathophysiology. Methods Immunohistochemistry was used to examine β-amyloid (Aβ) deposition along blood vessels, also known as cerebral amyloid angiopathy (CAA), fibrin(ogen) deposition, and their correlation to each other in the brains of AD patients with and without HHC. To study AD-HHC co-morbidity in detail, an AD mouse model was administered a high methionine diet for several months. Parenchymal Aβ plaques, CAA-positive vessels and fibrin deposits were then assessed by immunohistochemistry at different stages of AD progression. Memory deficits were evaluated with contextual fear conditioning and the Barnes maze. Additionally, the effect of HC and its metabolite, homocysteine thiolactone (HCTL), on the Aβ-fibrinogen interaction was analyzed by pull-down, ELISA and fibrin clot formation and fibrinolysis assays in vitro. Results We found increased fibrin(ogen) levels and Aβ deposits in the blood vessels and brain parenchyma of AD patients with HHC. We demonstrate that HC and HCTL enhance the interaction between fibrinogen and Aβ, promote the formation of tighter fibrin clots and delay clot fibrinolysis. Additionally, we show that diet-induced HHC in an AD mouse model leads to severe CAA and parenchymal Aβ deposition, as well as significant impairments in learning and memory. Conclusions These findings suggest that elevated levels of plasma HC/HCTL contribute to AD pathology via the Aβ-fibrin(ogen) interaction.