Environmental Factors Drive Neurodegenerative Diseases Through Glutamate Excitotoxicity: A Convergent Mechanistic Pathway
Yulu He1 · Tingting Yi1 · Meixin Min1 · Ke Xu1 · Huan Lin1 · Rong Xu2 · Dan Deng3 · Xiaoping Xiao1
1 Ganzhou Key Laboratory for Drug Screening and Discovery, Jiangxi Provincial Key Laboratory of Synthetic Pharmaceutical Chemistry, School of Geography and Environmental Engineering, Gannan Normal University, Ganzhou 341000, China
2 The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
3 Gannan Health Vocational College, Ganzhou 341000, China
Abstract
This review illustrates how environmental stressors disrupt glutamate homeostasis via specific mechanisms: lead-induced thiol modification, manganese mediated yin yang 1 (YY1)-histone deacetylases (HDAC) repression, PM2.5-triggered microglia-astrocyte crosstalk, and advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)-nuclear factor kappa-B (NF-κB) signaling from high-sugar diets. Together with genetic susceptibility and pigment epithelium-derived factor (PEDF), these factors impair astrocytic glutamate uptake, promoting synaptic glutamate accumulation. Subsequent N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor overactivation triggers calcium overload, mitochondrial dysfunction, oxidative stress, and neuroinflammation—termed "degenerative excitotoxicity". Excitotoxicity manifests in Alzheimer's disease (amyloid-beta-excitatory amino acid transporter 2 (EAAT2) interplay), Parkinson's disease (subthalamic nucleus-driven excitatory storm), and amyotrophic lateral sclerosis (astrocytic failure versus neuronal cell-autonomous mechanisms). Future interventions need multi-target strategies, emerging technologies, and lifestyle modifications. This convergent framework offers a unified understanding linking environmental exposure to neurodegeneration and charts a roadmap toward mechanism-based prevention and treatment.
Keywords
Neurodegenerative diseases; Glutamate; Excitotoxicity; Alzheimer’s disease; Parkinson’s disease; Amyotrophic lateral sclerosis
