ALTERATION OF THE G-PROTEIN GΑO SUBUNIT IN THE HIPPOCAMPUS IN AMYLOID-Β AND TAU PATHOLOGY

Heterotrimeric guanine nucleotide-binding proteins (G-proteins) transmit signals from G protein-coupled receptors (GPCRs) to intracellular effector systems that are disrupted in Alzheimer’s disease (AD). However, there is limited information on the specific changes in Gα subunits related to amyloidosis and tauopathy at the subcellular level.
Aims: To detect potential alterations in the protein levels and localization of Gαo in the brains of 5xFAD, APP/PS1, and P301S mice.
Methods: Histoblot and quantitative immunoelectron microscopic techniques.
Results: Histoblot analysis revealed that Gαo is widely distributed throughout the brain. We observed a significant downregulation of Gαo protein levels in the hippocampus of 5xFAD, APP/PS1, and P301S mice, particularly in the dendritic layers of the CA1 region, which was less pronounced in the context of tau pathology. Additionally, a reduction in Gαo was noted in the caudate putamen and cortex of 5xFAD mice. At the subcellular level, immunoelectron microscopy showed a significant decrease in the postsynaptic localization of Gαo along the extrasynaptic plasma membrane of dendritic spines and shafts in CA1 pyramidal cells across the three AD mouse models. However, the distribution of Gαo protein relative to glutamate release sites in dendritic spines was altered in 5xFAD and APP/PS1 mice, but not in P301S mice. Presynaptically, Gαo immunolabeling in axon terminals was significantly reduced in the three AD mouse models.
Conclusions: These reductions in Gαo at both postsynaptic and presynaptic sites suggest potential alterations in G protein-mediated signalling within hippocampal pyramidal cells, which may contribute to the cognitive dysfunctions observed in those transgenic mice.