Hyperhomocysteinemia exacerbates Alzheimer's disease pathology by way of the β‐amyloid fibrinogen interaction

Abstract

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 amyloid-beta (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 comorbidity 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.

High-throughput and simultaneous quantitative analysis of homocysteine–methionine cycle metabolites and co-factors in blood plasma and cerebrospinal fluid by isotope dilution LC–MS/MS

“…For instance, an imbalance of this metabolic pathway, marked by hyperhomocysteinemia and/or an altered SAM/SAH ratio, is a hallmark of memory loss and cognitive decline in elderly populations [34, 35] This loss of metabolic homeostasis may result from deficiency in metabolites and co-factors—such as vitamin B 12 or folic acid—directly and indirectly involved in the methylation of homocysteine. An increased interest exists to decipher their role as potential biomarkers of neurodegeneration in Alzheimer’s disease [36–38]. The robustness of our method for the sensitive detection and quantitation of the 17 metabolites and co-factors of methionine metabolism was assessed in biological materials collected from healthy donors and patients diagnosed with Alzheimer’s disease.…”

The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health

“…Moreover, the rate of cognitive decline positively correlated with the increased level tHcy in patients with the moderate stage of Alzheimer’s disease and they have stronger behavioral disturbances which could be associated with major depressive disorder [81,82]. Very recently was shown, that Hcy and Hcy-TL enhance the interaction between fibrinogen and amyloid β, promote the formation of tighter fibrin clots and delay clot fibrinolysis [83]. It has been also reported that dysfunctional folate-methionine pathway enzymes, mostly MTHFR polymorphisms C677T and A1298C, may play an important role in the pathophysiology of autism (MIM 209850) [84,85].…”

Fundamentals of fetal toxicity relevant to sevoflurane exposures during pregnancy

“…Homocysteine may be remethylated to methionine or converted to cysteine by the transsulfuration pathway. In triple transgenic mice, a high level of homocysteine increased brain b‐amyloid (Ab) levels and tau neuropathology and induced memory deficits (Li et al, 2014; Chung et al, 2016). Sevoflurane can disrupt methionine and cysteine metabolism, increasing beta‐amyloid and tau levels, eventually leading to neurological damage.…”