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Basic Science and Pathogenesis.

Quentin Bonomo1, Sonia Do Carmo1, Claudio A Cuello1

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Tau pathology in rats causes cholinergic system dysfunction and synaptic loss, independent of amyloidosis. This study reveals a tau-mediated impact on nerve growth factor (NGF) pathways, contributing to Alzheimer's disease progression.

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Area of Science:

  • Neuroscience
  • Pathology

Background:

  • Alzheimer's disease (AD) is the most common tauopathy, impacting millions.
  • The basal forebrain cholinergic system's atrophy is known in AD, but Tau's specific role is unclear.
  • This study uses a novel rat model to explore Tau's impact on cholinergic function without amyloidosis.

Purpose of the Study:

  • To investigate the role of brain tauopathy in cholinergic system dysregulation.
  • To assess Tau pathology's contribution to neurodegeneration in the cholinergic system.
  • To examine the relationship between Tau and nerve growth factor (NGF) metabolism.

Main Methods:

  • Utilized McGill-R955-hTau transgenic rats and Wild-type (WT) littermates.
  • Quantified vesicular acetylcholine transporter (VAChT) varicosities via immunohistochemistry to assess cholinergic innervation.
  • Analyzed NGF metabolic pathway proteins using Western Blot and ELISA.

Main Results:

  • Reduced VAChT immunoreactive varicosities observed in transgenic rats, indicating diminished cortical cholinergic innervation.
  • Significantly lower mature NGF levels and elevated proNGF and Neuroserpin levels in transgenic rats.
  • Evidence of impaired conversion of proNGF to mature NGF, suggesting compromised trophic support.

Conclusions:

  • The McGill-R955-hTau rat model shows tau-mediated cholinergic dysfunction and synaptic loss, independent of amyloidosis.
  • Findings highlight accelerated dysregulation of the NGF metabolic pathway by Tau pathology.
  • Provides insights into the mechanistic link between tauopathy and cholinergic atrophy in AD progression.