Cdc42GAP deficiency contributes to the Alzheimer’s disease phenotype

Abstract

Abstract Alzheimer’s disease, the most common cause of dementia, is a chronic degenerative disease with typical pathological features of extracellular senile plaques and intracellular neurofibrillary tangles and a significant decrease in the density of neuronal dendritic spines. Cdc42 is a member of the small G protein family that plays an important role in regulating synaptic plasticity and is regulated by Cdc42GAP, which switches Cdc42 from active GTP-bound to inactive GDP-bound states regulating downstream pathways via effector proteins. However, few studies have focused on Cdc42 in the progression of Alzheimer’s disease. In a heterozygous Cdc42GAP mouse model that exhibited elevated Cdc42-GTPase activity accompanied by increased Cdc42-PAK1-cofilin signalling, we found impairments in cognitive behaviours, neuron senescence, synaptic loss with depolymerization of F-actin and the pathological phenotypes of Alzheimer’s disease, including phosphorylated tau (p-T231, AT8), along with increased soluble and insoluble Aβ1–42 and Aβ1–40, which are consistent with typical Alzheimer’s disease mice. Interestingly, these impairments increased significantly with age. Furthermore, the results of quantitative phosphoproteomic analysis of the hippocampus of 11-month-old GAP mice suggested that Cdc42GAP deficiency induces and accelerates Alzheimer’s disease-like phenotypes through activation of GSK-3β by dephosphorylation at Ser9, Ser389 and/or phosphorylation at Tyr216. In addition, overexpression of dominant-negative Cdc42 in the primary hippocampal and cortical neurons of heterozygous Cdc42GAP mice reversed synaptic loss and tau hyperphosphorylation. Importantly, the Cdc42 signalling pathway, Aβ1–42, Aβ1–40 and GSK-3β activity were increased in the cortical sections of Alzheimer’s disease patients compared with those in healthy controls. Together, these data indicated that Cdc42GAP is involved in regulating Alzheimer’s disease-like phenotypes such as cognitive deficits, dendritic spine loss, phosphorylated tau (p-T231, AT8) and increased soluble and insoluble Aβ1–42 and Aβ1–40, possibly through the activation of GSK-3β, and these impairments increased significantly with age. Thus, we provide the first evidence that Cdc42 is involved in the progression of Alzheimer’s disease-like phenotypes, which may provide new targets for Alzheimer’s disease treatment.