A high circulating level of homocysteine (Hcy), also known as hyperhomocysteinemia, is a risk factor for Alzheimer’s disease (AD). Previous studies show that elevated Hcy promotes brain amyloidosis and behavioral deficits in mouse models of AD. However, whether it 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 with 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 5-lipoxygenase via cdk5 kinase pathway activation. Our findings support the novel concept that high Hcy level in the central nervous system is a metabolic risk factor for neurodegenerative diseases, specifically characterized by the progressive accumulation of tau pathology, namely tauopathies.
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Domenico Praticò is the Scott Richards North Star Charitable Foundation Chair for Alzheime'rs research. The work presented in this paper was in part supported by grants from the National Institute of Health (HL112966 and AG51684).
ADM and DP designed the study; ADM and JGL performed the experiments; CB and SM were involved in the measurement of Hcy SAM an SAH; ADM and DP analyzed the data and drafted the manuscript. All authors have discussed the results and seen the final version of the paper before submission.
Conflict of interest
The authors declare that they have no conflict of interest.
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Di Meco, A., Li, J., Barrero, C. et al. Elevated levels of brain homocysteine directly modulate the pathological phenotype of a mouse model of tauopathy. Mol Psychiatry 24, 1696–1706 (2019). https://doi.org/10.1038/s41380-018-0062-0
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