Rho GTPase-activating protein 44

ARHGAP44 (Rho GTPase-activating protein 44) is a GAP protein that regulates Rho-type GTPases, particularly CDC42 and RAC1, by stimulating their GTPase activity and controlling their cycling between active GTP-bound and inactive GDP-bound states (UniProt: Q17R89). In neurons, the protein plays a role in dendritic spine formation and synaptic plasticity through RAC1-GAP activity, limiting exploratory dendritic filopodia initiation and regulating actin polymerization at the plasma membrane. ARHGAP44 also associates with SHANK3 to promote GRIA1 exocytosis and spine morphological changes linked to long-term potentiation (UniProt: Q17R89).

In Alzheimer's Disease, ARHGAP44 is downregulated in post-mortem AD brain tissue compared to age-matched controls, with a mean log2 fold-change of −0.47 (Chaparral AD proteomics). This reduction was observed in human post-mortem AD brain samples analyzed by TMT-labeled proteomics across four subcellular fractions. The downregulation of this synaptic plasticity-related protein may contribute to the dendritic spine loss and cognitive dysfunction characteristic of AD pathology.