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Behavioral Abnormalities in Knockout and Humanized Tau Mice.

Rafaella Araujo Gonçalves1,2, Nadeeja Wijesekara2, Paul E Fraser2,3

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The tau protein is crucial for memory and anxiety regulation. Its absence in mice leads to anxiety and memory deficits, highlighting its non-CNS roles and impact on Alzheimer's disease research.

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Area of Science:

  • Neuroscience
  • Metabolic Research
  • Molecular Biology

Background:

  • Microtubule-associated protein tau is vital for microtubule stability and implicated in Alzheimer's disease (AD).
  • Previous research suggests tau influences peripheral metabolic regulation, but its roles in anxiety and memory are less understood.
  • Understanding tau's non-central nervous system (CNS) functions is critical for AD pathogenesis and therapeutic development.

Purpose of the Study:

  • To investigate the role of tau protein in anxiety-related behaviors, memory, and systemic insulin resistance.
  • To compare phenotypes in Wild-Type (WT), Tau knockout (TauKO), and human tau (hTau) transgenic mouse models.
  • To elucidate the impact of tau deletion and human tau expression on cognitive and metabolic functions.

Main Methods:

  • Characterization of anxiety-related behavior, contextual and cued fear memory, and systemic insulin resistance in WT, TauKO, and hTau mice (15-20 weeks old).
  • Utilized behavioral assays and metabolic assessments to evaluate the functional consequences of tau manipulation.
  • Compared phenotypes across different mouse models to isolate the effects of mouse tau and human tau expression.

Main Results:

  • Tau deletion in mice resulted in significant anxiety-related behavior and impaired contextual and cued fear memory.
  • The presence of a human tau transgene did not rescue these deficits and introduced additional impairments in learning, memory, and insulin sensitivity.
  • Tau knockout mice exhibited systemic insulin resistance, indicating a role for tau in peripheral metabolic regulation.

Conclusions:

  • Tau protein plays a significant role in regulating memory and anxiety-related behaviors.
  • Tau deletion has detrimental effects on cognitive function and peripheral insulin sensitivity.
  • The findings suggest that tau's non-CNS functions are important and that TauKO models may have confounding factors due to uncharacterized roles of tau protein.