Elevated levels of brain homocysteine directly modulates the pathological phenotype of a mouse model of tauopathy

High circulating level of homocysteine (Hcy), also known as hyper-homocysteinemia, is a risk factor for Alzheimer’s disease (AD). Previous studies showed that elevated Hcy promotes brain amyloidosis and behavioral deficits in mouse models of AD. However, whether it also directly modulates the development of tau neuropathology independently of amyloid-beta in vivo is unknown. Herein we investigate the effect of diet-induced elevated levels of brain Hcy on the phenotype of a relevant mouse model of human tauopathy. Compared with controls, tau mice fed low folate and B vitamins diet, had a significant increase in brain Hcy levels and worsening of behavioral deficits. The same mice had a significant elevation of tau phosphorylation, synaptic pathology and astrocytes activation. In vitro studies demonstrated that Hcy effect on tau phosphorylation was mediated by an upregulation of the 5-lipoxygenase via cdk5 kinase pathway activation. Our findings support the novel concept that high Hcy levels in the central nervous system is a metabolic risk factor also for neurodegenerative diseases specifically characterized by the progressive accumulation of tau pathology, namely tauopathies.