中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (6): 2370-2383.doi: 10.4103/NRR.NRR-D-25-00144

• 综述:退行性病与再生 • 上一篇    下一篇

代谢分解:胰岛素抵抗和线粒体功能障碍与阿尔茨海默病神经变性的关联

  

  • 出版日期:2026-06-15 发布日期:2025-09-18

Metabolic breakdown: Linking insulin resistance and mitochondrial dysfunction to neurodegeneration in Alzheimer’s disease

Simona Lanzillotta, Lucrezia Romana Rolfi# , Barbara Zulli# , Eugenio Barone*   

  1. Department of Biochemical Sciences “A. Rossi-Fanelli”, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy
  • Online:2026-06-15 Published:2025-09-18
  • Contact: Eugenio Barone, PharmD, PhD, eugenio.barone@uniroma1.it.
  • Supported by:
    This work was supported by Fondi Ateneo grants funded by Sapienza University (#RM120172A3160B53) to EB and funds from Jerome-Lejeune Foundation (#1887-2019b) to EB; the EuropeanUnion – NextGenerationEU (Project ECS 0000024Rome Technopole, – CUP B83C22002820006, NRPMission 4 Component 2 Investment 1.5 to LRR).

摘要: https://orcid.org/0000-0002-7028-4251 (Eugenio Barone)

Abstract: The increasing prevalence of metabolic disorders and neurodegenerative diseases has uncovered shared pathophysiological pathways, with insulin resistance and mitochondrial dysfunction emerging as critical contributors to cognitive decline. Insulin resistance impairs neuronal metabolism and synaptic function, fostering neurodegeneration as observed in Alzheimer’s disease and Down syndrome. Indeed, Down syndrome, characterized by the triplication of the APP gene, represents a valuable genetic model for studying early-onset Alzheimer’s disease and accelerated aging. Building on the link between metabolic dysfunctions and neurodegeneration, innovative strategies addressed brain insulin resistance as a key driver of cognitive decline. Intranasal insulin has shown promise in improving cognition in early Alzheimer’s disease and type 2 diabetes, supporting the concept that restoring insulin sensitivity can mitigate neurodegeneration. However, insulin-based therapies risk desensitizing insulin signaling, potentially worsening the disease. Incretins, particularly glucagonlike peptide 1 receptor agonists, offer neuroprotective benefits by enhancing insulin sensitivity, metabolism, and synaptic plasticity while reducing oxidative distress and neuroinflammation. This review focuses on current knowledge on the metabolic and molecular interactions between insulin resistance, mitochondrial dynamics (including their roles in energy metabolism), and oxidative distress regulation, as these are pivotal in both Alzheimer’s disease and Down syndrome. By addressing these interconnected mechanisms, innovative treatments may emerge for both metabolic and neurodegenerative disorders.

Key words: aging, Alzheimer’s disease, brain insulin resistance, Down syndrome, energy metabolism, glucagon-like peptide 1, incretins, insulin, mitochondria, neurodegeneration