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

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 p38 alpha to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38 alpha 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 p38 alpha only in neurons (5XFAD/p38 alpha Delta-N). We found that the neuronal-specific deletion of p38 alpha improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38 alpha Delta-N mice display reduced amyloid-beta accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38 alpha signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-beta deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits.