Cdc42GAP deficiency contributes to the Alzheimer's disease phenotype

Topic: Disease mechanisms in lab and animal studies

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.

Key findings

• 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.
• 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.
• 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.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1093/brain/awad184
• PubMed: 37254741
• Original source →

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@article{zhu2023-37254741,
  author  = {Zhu, Mengjuan and Xiao, Bin and Xue, Tao and Qin, Sifei and Ding, Jiuyang and Wu, Yue and Tang, Qingqiu and Huang, Mengfan and others},
  title   = {{Cdc42GAP deficiency contributes to the Alzheimer's disease phenotype}},
  journal = {Brain : a journal of neurology},
  year    = {2023},
  doi     = {10.1093/brain/awad184},
  pmid    = {37254741},
  url     = {https://doi.org/10.1093/brain/awad184}
}

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