PR-957 Suppresses Th1 and Th17 Cell Differentiation via Inactivating PI3K/AKT Pathway in Alzheimer’s Disease

PR-957 [low molecular mass polypeptide (LMP)-7 selective inhibitor] regulates T helper (Th) cell differentiation and inflammatory response in multiple neurological diseases. Hence, this study aimed to explore the effect of PR-957 on Th1/Th2/Th17 cell differentiation, therapeutic efficacy and its potential mechanisms in Alzheimer's disease (AD). The LMP7 expressions in peripheral blood mononuclear cells from 30 AD patients and 30 healthy controls (HC) were detected. PR-957 was added for the incubation of naive cluster of differentiation (CD)4+ T cells from AD patients, then SC79 [phosphorylated protein kinase B (pAKT) agonist] was added. LMP7, Th1 cells, and Th17 cells were upregulated, while Th2 cells were downregulated in AD patients compared to HC. Also, LMP7 was positively related to Th1 cells and Th17 cells, but it did not correlate with Th2 cells in AD patients. PR-957 treatment downregulated Th1 cells, Th17 cells, and their secreted cytokines as well as phosphorylated phosphoinositide 3-kinase (pPI3K)/PI3K and pAKT/AKT expressions in AD CD4+ T cells. SC79 addition upregulated pAKT/AKT expression, Th1 cells, and Th17 cells, while downregulated Th2 cells; also SC79 could alleviate the effect of PR-957 on regulating PI3K/AKT pathway and Th1, Th2, and Th17 cell differentiation in AD CD4+ T cells. Furthermore, PR-957 attenuated cognitive impairment and neurofibrillary tangle; also it inhibited Th17 cell differentiation and PI3K/AKT pathway in the brain and spleen of AD mice. In conclusion, PR-957 suppresses Th1 and Th17 cell differentiation, attenuates neural injury and improves cognitive function via inactivating PI3K/AKT pathway in AD.