Cdc42GAP deficiency contributes to the Alzheimer's disease phenotype.

Alzheimer's disease (AD), the most common cause of dementia, is a chronic degenerative disease with typical pathological features of extracellular senile plaques and intracellular neurofibrillary tangles with 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 signaling, we found impairments in cognitive behaviors, neuron senescence, synaptic loss with depolymerization of F-actin and the pathological phenotypes of Alzheimer's disease, including phosphorylated tau (p-T231, AT8), increased soluble and insoluble Aβ1-42 and Aβ1-40, which are consistent with typical Alzheimer's disease mice. Interestingly, these impairments increase significantly with age. Furthermore, the results of quantitative phosphoproteomic analysis of the hippocampus of 11-month-old GAP mice suggest that Cdc42GAP deficiency induces and accelerates Alzheimer's disease-like phenotypes through activating GSK-3β by dephosphorylation at Ser-9, Ser-389 and/or phosphorylation at Tyr-216. 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 signaling pathway, Aβ1-42, Aβ1-40 and the activity of GSK-3β were increased in the cortical sections of Alzheimer's disease patients compared with those in healthy controls. Together, these data indicate 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 activating GSK-3β. In addition, these impairments increase significantly with age. Thus, we provide the first evidence that the Cdc42 is involved in the progression of Alzheimer's disease-like phenotypes, which may provide new targets for Alzheimer's disease treatment.