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Basic Science and Pathogenesis.

Dibyadeep Datta1, Dinara Bolat1, Isabella Perone1

  • 1Yale University, New Haven, CT, USA.

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Summary
This summary is machine-generated.

Phosphorylated tau (pT217-tau) aggregates in dendrites, indicating early neuronal degeneration and potential seeding of Alzheimer's disease pathology. This finding explains why pT217-tau is an effective biomarker for predicting Alzheimer's disease.

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Area of Science:

  • Neuroscience
  • Biomarker Discovery
  • Alzheimer's Disease Research

Background:

  • A novel fluid biomarker, pT217-tau, predicts Alzheimer's disease (AD) before cognitive decline.
  • Understanding pT217-tau's role in brain pathology is crucial for early AD treatment efficacy.
  • Early-stage soluble pT217-tau brain expression and its link to neurodegeneration markers remain unclear.

Purpose of the Study:

  • To investigate the subcellular localization and function of early-stage pT217-tau in the aging rhesus macaque brain.
  • To elucidate the relationship between pT217-tau and markers of neurodegeneration and tau pathology.
  • To understand the mechanism by which pT217-tau predicts AD pathology.

Main Methods:

  • Utilized multi-label immunofluorescence and immunoelectron microscopy.
  • Examined subcellular localization of pT217-tau in the entorhinal cortex (ERC) and dorsolateral prefrontal cortex (dlPFC) of aged macaques.
  • Investigated naturally occurring tau pathology in a non-human primate model of sporadic AD.

Main Results:

  • pT217-tau localizes to dendrites of excitatory neurons, co-expressing with markers of autophagic vacuolar degeneration, endo-lysosomal dysfunction, and neurodegeneration.
  • pT217-tau accumulates in postsynaptic compartments, including dendritic spines and shafts, interacting with microtubules and endosomes.
  • Trans-synaptic trafficking of pT217-tau was observed between neurons near excitatory synapses.

Conclusions:

  • Early-stage pT217-tau aggregates on microtubules, disrupts endosomal trafficking, and contributes to dendritic degeneration and neuronal dysfunction.
  • pT217-tau traffics between neurons, potentially seeding tau pathology in higher brain circuits and becoming accessible to CSF and blood.
  • Dendritic expression of pT217-tau with early degeneration signs explains its predictive power for future Alzheimer's disease.