No abstract

Substantial spine loss in striatal medium spiny neurons (MSNs) and abnormal behaviors are common features of Parkinson's disease (PD). The caudate putamen (CPu) mainly contains MSNs expressing dopamine D1 receptor (dMSNs) and dopamine D2 receptor (iMSNs) exerting critical effects on motor and cognition behavior. However, the molecular mechanisms contributing to spine loss and abnormal behaviors in dMSNs and iMSNs under parkinsonian state remain unknown. In the present study, we revealed that Cell division control protein 42 (Cdc42) signaling was significantly decreased in the caudate putamen (CPu) in parkinsonian mice. In addition, overexpression of constitutively active Cdc42 in the CPu reversed spine abnormalities and improved the behavior deficits in parkinsonian mice. Utilizing conditional dopamine D1 receptor (D1R) or D2 receptor (D2R) knockout mice, we found that such a decrease under parkinsonian state was further reduced by conditional knockout of the D2R but not D1R. Moreover, the thin spine loss in iMSNs and deficits in motor coordination and cognition induced by conditional knockout of D2R were reversed by overexpression of constitutively active Cdc42 in the CPu. Additionally, conditional knockout of Cdc42 from D2R‐positive neurons in the CPu was sufficient to induce spine and behavior deficits similar to those observed in parkinsonian mice. Overall, our results indicate that impaired Cdc42 signaling regulated by D2R plays an important role in spine loss and behavioral deficits in PD.

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.