A prolyl oligopeptidase ligand blocks memory deficit in a repeated mild traumatic brain injury model

Traumatic brain injury (TBI) impacts up to 60 million people annually. Both severe TBIs and repeated mild TBIs (rmTBIs) can lead to persistent symptoms such as cognitive deficits, and even neurodegenerative diseases like chronic traumatic encephalopathy (CTE). To date, no therapies exist to mitigate the risk of CTE or other chronic symptoms post-TBI. Tau protein accumulation plays a pivotal role in the development of CTE. Recent studies indicate that small-molecular ligands targeting prolyl oligopeptidase (PREP) can decrease Tau accumulation through the activation of protein phosphatase 2 A (PP2A). This led us to investigate whether PREP ligands could alleviate behavioural deficits in an rmTBI mouse model. In our study, mice subjected to five closed-head impacts at 24-h intervals were treated after each hit with either a typical PREP inhibitor, KYP-2047, or a novel PREP ligand, HUP-46. PREP knock-out mice also underwent similar impacts. Results demonstrated significant cognitive deficits in rmTBI mice as measured by the Barnes Maze at a 3-month endpoint. However, HUP-46 successfully mitigated these cognitive deficits, and PREP knock-out mice showed resistance to rmTBI-induced cognitive impairments. HUP-46 notably reduced rmTBI-induced astrogliosis and the levels of p21, a cell-cycle inhibitor and a cellular senescence marker connected with aging-related diseases, in the cortex. Additionally, PREP ligands diminished the phosphorylation of calcium/calmodulin-dependent protein kinase type II (CaMKII) shortly after rmTBI. While Tau accumulation was observed only in the dorsal fornix-an essential white matter tract for hippocampal connectivity-PREP ligands did not significantly affect this accumulation. Collectively, these findings suggest that PREP ligands could serve as a therapeutic intervention post-TBI to lower long-term risks.