PSEN1 and Alzheimer disease: To investigate the role of neuronal p38α in AD-like phenotypic traits in vivo, we have used the five familial AD mutations (5XFAD) model, which overexpresses mutant human APP and presenilin-1 (PS1), and rapidly develops severe amyloid pathology followed by synapse degeneration and cognitive deficits28, 29, 30.