1. Academic Validation
  2. Neuronal aerobic glycolysis exacerbates synapse loss in aging mice

Neuronal aerobic glycolysis exacerbates synapse loss in aging mice

  • Exp Neurol. 2023 Oct 29:371:114590. doi: 10.1016/j.expneurol.2023.114590.
Wenhui Zhou 1 Xingyue Yang 1 Huixia Wang 1 Wenjuan Yao 1 Dandan Chu 2 Feng Wu 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China.
  • 2 Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China. Electronic address: chudd@ntu.edu.cn.
  • 3 Department of Pharmacology, School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China. Electronic address: wf619@ntu.edu.cn.
Abstract

Brain consumes nearly 20% supply of energy from glucose metabolism by Oxidative Phosphorylation and aerobic glycolysis. Less active state of glycolytic Enzymes results in a limited capacity of glycolysis in the neurons of adult brain. Here we identified that Warburg effect is enhanced in hippocampal neurons during aging. As hippocampal neurons age, lactate levels progressively increase. Notably, we observed upregulated protein levels of PFKFB3 in the hippocampus of 20-month-old mice compared to young mice, and this higher PFKFB3 expression correlated with declining memory performance in aging mice. Remarkably, in aging mice, knocking down Pfkfb3 in hippocampal neurons rescued cognitive decline and synapse loss. Conversely, Pfkfb3 overexpression in hippocampal neurons led to cognitive impairment and synapse elimination, associated with heightened glycolysis. In vitro experiments with cultured primary neurons confirmed that Pfkfb3 overexpression increased glycolysis and that glycolytic inhibition could prevent apoptotic competency in neurons. These findings underscore that glycolysis in hippocampal neurons could potentially be targeted as a therapeutic avenue to mitigate cognitive decline and preserve synaptic integrity during aging.

Keywords

Aerobic glycolysis; Aging; Cognitive decline; PFKFB3; Synapse loss.

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