Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer's mouse model by controlling β-amyloid production

Sci Rep. 2017 Mar 31:7:45306. doi: 10.1038/srep45306.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38α to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38α signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38α only in neurons (5XFAD/p38α∆-N). We found that the neuronal-specific deletion of p38α improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38α∆-N mice display reduced amyloid-β accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38α signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-β deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / psychology*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Cells, Cultured
  • Cognitive Dysfunction / metabolism*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Down-Regulation
  • Gene Deletion
  • Humans
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 14 / deficiency
  • Mitogen-Activated Protein Kinase 14 / genetics*
  • Neuronal Plasticity
  • Neurons / cytology
  • Neurons / metabolism*
  • Signal Transduction

Substances

  • Amyloid beta-Peptides
  • Cytokines
  • Mitogen-Activated Protein Kinase 14