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Di Meco A , Li JG , Barrero C , Merali S , Pratico D
Elevated levels of brain homocysteine directly modulate the pathological phenotype of a mouse model of tauopathy
Mol Psychiatry. 2019 Nov;24(11) :1696-1706
PMID: 29728702    PMCID: PMC6215750    URL: https://www.ncbi.nlm.nih.gov/pubmed/29728702
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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.
1476-5578 Di Meco, Antonio Li, Jian-Guo Barrero, Carlos Merali, Salim Pratico, Domenico R01 HL112966/HL/NHLBI NIH HHS/United States RF1 AG051684/AG/NIA NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England Mol Psychiatry. 2019 Nov;24(11):1696-1706. doi: 10.1038/s41380-018-0062-0. Epub 2018 May 4.