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VPS35 regulates tau phosphorylation and neuropathology in tauopathy

Alana N Vagnozzi1, Jian-Guo Li1, Jin Chiu1

  • 1Alzheimer's Center at Temple, Department of Pharmacology, Philadelphia, PA, 19140, USA.

Molecular Psychiatry
|July 11, 2019
PubMed

Insights

Vacuolar protein sorting 35 (VPS35) deficiency is linked to tauopathies. Reduced VPS35 exacerbates tau pathology and cognitive deficits, identifying VPS35 as a therapeutic target for neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Genetics

Background:

  • Vacuolar protein sorting 35 (VPS35) is crucial for intracellular trafficking and linked to Alzheimer's disease via APP/Aβ metabolism.
  • VPS35 levels are notably decreased in tauopathies like Progressive Supranuclear Palsy and Pick's disease.

Purpose of the Study:

  • To investigate the role of VPS35 in tau metabolism and neuropathology.
  • To explore VPS35 as a potential therapeutic target for tauopathies.

Main Methods:

  • In vitro studies involving overexpression and genetic silencing of VPS35 in neuronal cells.
  • Analysis of VPS35 levels in human tauopathy tissues.
  • Assessment of motor and learning functions, tau pathology, and synaptic integrity in a transgenic mouse model of tauopathy.

Main Results:

  • VPS35 overexpression reduced pathological tau, while VPS35 silencing increased tau accumulation, mediated by cathepsin D.
  • VPS35 down-regulation in a mouse model worsened motor and learning impairments, elevated pathological tau, and caused synaptic damage.

Conclusions:

  • VPS35 plays a critical role in regulating tau metabolism and neuropathology.
  • VPS35 represents a novel therapeutic target for human tauopathies.

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