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Basic Science and Pathogenesis.

Diede Broekaart1, Abhijeet Sharma1, Aarthi Ramakrishnan1

  • 1Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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|December 24, 2025
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Summary
This summary is machine-generated.

Excitatory neurons are most vulnerable to tau pathology in tauopathies. Altered neurotransmission and synaptic changes, possibly driven by Mef2c, contribute to this selective vulnerability and neurodegeneration.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Tauopathies involve hyperphosphorylated tau protein aggregation, leading to cognitive decline.
  • Pathological tau spreads through specific brain regions and neuronal types, but mechanisms of selective vulnerability remain unclear.

Purpose of the Study:

  • To investigate the cellular and molecular mechanisms underlying selective neuronal vulnerability in tauopathies.
  • To identify key molecular players contributing to regional susceptibility to tau pathology.

Main Methods:

  • Immunohistochemistry on post-mortem human brain tissue from tauopathies.
  • Viral translating ribosome affinity purification (vTRAP) in P301S (PS19) mice and controls.
  • RNA sequencing, bioinformatics (Gene Ontology, MECT), and electrophysiological characterization.

Main Results:

  • Excitatory neurons show predominant tau accumulation compared to inhibitory neurons across various tauopathies.
  • Vulnerable neurons and regions exhibit altered synaptic transmission and neuronal excitability.
  • Mef2c identified as a regulator of myelination and synaptic organization in vulnerable regions; findings validated in human tauopathies.

Conclusions:

  • Excitatory neurons are the primary target of tau pathology in tauopathies.
  • Selective vulnerability is linked to altered neurotransmission and synaptic composition, potentially regulated by Mef2c.
  • This study elucidates molecular drivers of regional and cellular susceptibility in neurodegeneration.