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ApoE3 binding to tau tandem repeat I is abolished by tau serine262 phosphorylation
D Y Huang1, K H Weisgraber, M Goedert
1Department of Medicine (Neurology), Joseph and Kathleen Bryan Alzheimer's Disease Research Center, Duke University Medical Center, Durham, NC 27710, USA.
Abstract:
The risk of Alzheimer's disease is determined, in part, by inheritance of specific alleles of ApoE. Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease. Synthetic peptides representing each of the four microtubule-binding domains of tau more avidly bind ApoE3 than ApoE4. Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3. Understanding the molecular mechanisms of the high avidity, isoform-specific interactions of ApoE with tau may help in developing approaches for disease intervention.
Insights
Apolipoprotein E (ApoE) interactions with tau protein differ by ApoE type, influencing Alzheimer's disease risk. Understanding these specific binding mechanisms is key for developing new therapeutic strategies.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) risk is linked to apolipoprotein E (ApoE) alleles.
- ApoE interacts with tau protein, a component of neurofibrillary tangles in AD.
Purpose of the Study:
- To investigate the isoform-specific binding of ApoE to tau protein.
- To understand how tau phosphorylation affects ApoE binding.
Main Methods:
- Used synthetic peptides representing tau's microtubule-binding domains.
- Assessed binding avidity of ApoE3 and ApoE4 to these tau peptides.
- Examined the effect of tau phosphorylation at serine262 on ApoE binding.
Main Results:
- ApoE3 showed higher binding avidity to tau peptides than ApoE4.
- Phosphorylation of tau at serine262 reduced tau's binding to microtubules.
- Phosphorylation at serine262 abolished ApoE3 binding to tau.
Conclusions:
- ApoE isoform-specific interactions with tau are significant in Alzheimer's disease.
- Tau phosphorylation at serine262 disrupts ApoE binding, impacting disease mechanisms.
- Further research into these molecular interactions may guide AD interventions.