Stabilization of microtubules improves cognitive functions and axonal transport of mitochondria in Alzheimer's disease model mice

Neurobiol Aging. 2020 Dec;96:223-232. doi: 10.1016/j.neurobiolaging.2020.09.011. Epub 2020 Sep 12.

Abstract

One major pathological process in Alzheimer's disease is mediated by hyperphosphorylated tau, which includes altered microtubules (MTs) and functions associated with tau. A potential way to compensate for altered MT function is to use an MT stabilizer, such as epothilone D (EpoD). Previous studies have demonstrated improved cognitive functions and axonal transport by EpoD in tau-mutation mice. Here, we demonstrated that extended EpoD treatment also has beneficial effects on APP/PS1 double-transgenic mice, improving their motor and spatial memory, increasing key synaptic protein levels, while not affecting amyloid plaque density or level of tau phosphorylation. Interestingly, EpoD appears to improve the retrieval of formed memories. We also observed improved axonal transport of mitochondria in cultured neurons from APP/PS1 mice. In addition, higher level of perineuronal nets are found in APP/PS1 mice injected with EpoD, suggesting potential contributions of increased inhibition. Our results suggest potential therapeutic value of EpoD in treating Alzheimer's disease.

Keywords: Alzheimer's disease; Memory retrieval; Microtubule; Mitochondrial mobility; Perineuronal nets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / etiology
  • Alzheimer Disease / psychology*
  • Animals
  • Axonal Transport / drug effects*
  • Cells, Cultured
  • Cognition / drug effects*
  • Disease Models, Animal
  • Epothilones / pharmacology*
  • Epothilones / therapeutic use*
  • Memory / drug effects*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubules / pathology*
  • Microtubules / physiology
  • Mitochondria / metabolism*
  • Molecular Targeted Therapy
  • Phosphorylation
  • Stimulation, Chemical
  • tau Proteins / metabolism

Substances

  • Epothilones
  • tau Proteins
  • desoxyepothilone B