The role and mechanism of TPK‐SENP1 signaling axis in regulating Aβ deposition in Alzheimer’s disease

Abstract

AbstractBackgroundNumerous studies have demonstrated that SUMOylation plays an important role in the development of Alzheimer’s disease (AD). However, there has been no research on how key neural signals regulate the dynamic balance of target SUMOylation/deSUMOylation in AD. Therefore, further investigation is needed to explore important SUMOylation/deSUMOylation homeostatic regulatory targets and their mechanisms in AD.MethodAlterations in neurons, glia, and apoptosis were evaluated using immunofluorescence staining. The expression of related proteins was investigated using western blotting. Aβ40 and Aβ42 levels were measured using ELISA. An AAV carrying the Syn‐eGFP‐SENP1 construct was injected into the ventricles of mice. Behavioral assessments, including the Y maze and Rotarod tests, were performed to evaluate cognitive and motor function.ResultOur findings indicate that the expression of thiamine pyrophosphokinase (TPK) is significantly diminished in the brains of AD patients. The conditional ablation of TPK in the brains of adult mice results in the emergence of a range of AD‐like pathological features. Additionally, we observed a significant decrease in the expression of SUMO‐specific protease 1 (SENP1), suggesting that TPK may play a role in regulating SENP1 expression. The overexpression of SENP1 was able to ameliorate the AD‐like pathological features observed in TPK knockout mice. Furthermore, we found that levels of APP, BACE1, and Aβ were elevated in SENP1flox/flox; Camk2α‐Cre mice relative to control mice, providing further evidence for the critical role of SENP1 in AD pathogenesis.ConclusionModulation of SENP1 expression by TPK may regulate pathological features associated with AD, suggesting that SENP1 may be an important target for the development of AD drugs.