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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Phosphorylated tau exhibits antimicrobial activity capable of neutralizing herpes simplex virus 1 infectivity in
William A Eimer1,2, Alex S Rodriguez3,4, Michael T DeFao3,4
1Genetics and Aging Research Unit, Henry and Allison McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA. weimer@mgh.harvard.edu.
Abstract:
Tau is a microtubule-associated cytoskeletal protein, which, when hyperphosphorylated and aggregated, can result in a myriad of different tauopathies, including Alzheimer's disease (AD). We previously showed that the principal component of senile plaques, amyloid beta (Aβ), is an antimicrobial peptide capable of binding and entrapping microbial pathogens. Here we show that tau is hyperphosphorylated in neurons in response to viral infection and can neutralize herpes simplex virus 1 (HSV-1) infectivity by directly binding to viral capsids. Our data suggest that the 'pathogenic' characteristics of tau hyperphosphorylation, microtubule destabilization and aggregation are part of an antiviral response, in which tau serves as a host defense protein in the innate immune system of the brain. The combined antimicrobial activities of Aβ and phosphorylated tau resulting in Aβ plaques and neurofibrillary tangles, along with neuroinflammation, suggest that AD neuropathology may have evolved as an orchestrated innate immune host defense response to microbial infection in the brain.
Insights
The study reveals that tau protein hyperphosphorylation, a hallmark of Alzheimer's disease (AD), acts as an antiviral defense mechanism. This innate immune response neutralizes viral infections like herpes simplex virus 1 (HSV-1) in the brain.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Tau protein is a microtubule-associated protein implicated in tauopathies like Alzheimer's disease (AD) when hyperphosphorylated and aggregated.
- Amyloid beta (Aβ), a key component of senile plaques, exhibits antimicrobial properties.
- The role of tau in the brain's innate immune response remains incompletely understood.
Purpose of the Study:
- To investigate the role of tau hyperphosphorylation in neuronal response to viral infection.
- To determine if tau can neutralize viral infectivity.
- To explore the potential of tau as a host defense protein in the brain's innate immune system.
Main Methods:
- Investigated tau hyperphosphorylation in neurons following viral infection.
- Assessed the direct binding of tau to viral components, specifically herpes simplex virus 1 (HSV-1) capsids.
- Analyzed the functional consequences of tau-viral interactions on viral infectivity.
Main Results:
- Tau protein undergoes hyperphosphorylation in neurons in response to viral infection.
- Hyperphosphorylated tau directly binds to HSV-1 capsids, neutralizing its infectivity.
- Microtubule destabilization and tau aggregation appear to be components of an antiviral response.
Conclusions:
- Tau functions as a host defense protein within the brain's innate immune system.
- Alzheimer's disease neuropathology, including Aβ plaques and neurofibrillary tangles, may represent an evolved immune response to microbial infections.
- The combined antimicrobial actions of Aβ and phosphorylated tau suggest a coordinated host defense against brain infections.
