Homocysteine Increases Tau Phosphorylation, Truncation and Oligomerization

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Elevated plasma homocysteine is a known risk factor for dementia, including Alzheimer's disease (AD) and vascular dementia.
• The precise mechanisms linking hyperhomocysteinemia to dementia pathogenesis, particularly concerning tau pathology, remain unclear.
• Neurofibrillary tangles, composed of hyperphosphorylated tau, are a hallmark of AD.

Purpose of the Study:

• To investigate the effects of homocysteine (Hcy) on tau protein phosphorylation, truncation, aggregation, and cytotoxicity.
• To elucidate the molecular pathways involved in Hcy-induced tau pathology.
• To assess the therapeutic potential of S-adenosylmethionine in mitigating Hcy-induced tau changes.

Main Methods:

• In vitro studies using human neuroblastoma cells expressing wild-type tau.
• Primary mouse cultured neurons exposed to varying Hcy concentrations.
• In vivo studies using a mouse model of tauopathy with induced hyperhomocysteinemia (HHCy mice).
• Biochemical assays to measure total tau, phosphorylated tau, truncated tau (TauC3), and oligomeric tau (TOC1).
• Enzyme activity assays for tau phosphokinases and phosphatases, and caspase activation.

Main Results:

• Homocysteine significantly increased total tau and phosphorylated tau levels in vitro and in vivo.
• Hcy activated major tau phosphokinases (GSK3β, CDK5) and inactivated a key tau phosphatase (PP2A).
• Hcy induced tau truncation via caspase 3 activation (increased D421 cleavage) and promoted tau oligomerization and aggregation.
• Levels of oligomeric tau were elevated in HHCy mice brains.
• S-adenosylmethionine treatment reduced oligomeric tau levels in HHCy mice.

Conclusions:

• Homocysteine exacerbates tau pathology by increasing tau phosphorylation and truncation.
• Hcy-induced tauopathy involves the activation of caspase 3 and subsequent tau cleavage.
• Hcy promotes the formation of toxic tau oligomers and aggregates, contributing to dementia risk.
• S-adenosylmethionine may offer a therapeutic strategy to counteract Hcy-mediated tau pathology.