SENP1 inhibits aerobic glycolysis in Aβ1-42-incubated astrocytes by promoting PUM2 deSUMOylation.

Abstract

Alzheimer's disease (AD), the most prevalent form of dementia in the elderly, involves critical changes such as reduced aerobic glycolysis in astrocytes and increased neuronal apoptosis, both of which are significant in the disease's pathology. In our study, astrocytes treated with amyloid β1-42 (Aβ_1-42) to simulate AD conditions exhibited upregulated expressions of small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1) and Pumilio RNA Binding Family Member 2 (PUM2), alongside decreased levels of Nuclear factor erythroid 2-related factor 2 (NRF2). SENP1 is notably the most upregulated SUMOylation enzyme in Aβ_1-42-exposed astrocytes. Functional assays including Ni²⁺-Nitrilotriacetic acid (NTA) agarose bead pull-down and co-immunoprecipitation (Co-IP) confirmed SENP1's role in actively deSUMOylating PUM2, thereby enhancing its stability and expression. The interaction between PUM2 and the 3' untranslated region (3'UTR) of NRF2 mRNA reduces NRF2 levels, subsequently diminishing the transcriptional activation of critical glycolytic enzymes, Hexokinase 1 (HK1) and Glucose Transporter 1 (GLUT1). These changes contribute to the observed reduction in glycolytic function in astrocytes, exacerbating neuronal apoptosis. Targeted interventions, such as knockdown of Senp1 or Pum2 or overexpression of NRF2 in APPswe/PSEN1dE9 (APP/PS1) transgenic mice, effectively increased HK1 and GLUT1 levels, decreased apoptosis, and alleviated cognitive impairment. These findings highlight the important roles of the SENP1/PUM2/NRF2 pathway in influencing glucose metabolism in astrocytes, presenting new potential therapeutic targets for AD.