From Neuron-Glia Interaction to Metabolic Coupling Failure in Neurodegeneration

Brain function has traditionally been interpreted within a neuron-centric framework; however, this view has shifted toward a model of neuron-glia interaction, in which neurons, astrocytes, microglia, and oligodendrocytes form interdependent cellular networks that sustain synaptic and metabolic homeostasis. In the healthy brain, astrocytes regulate neurotransmitter cycling and provide metabolic substrates, microglia modulate synaptic structure, and oligodendrocytes support axonal function, collectively maintaining network stability.In neurodegenerative diseases such as Alzheimer’s disease, dysfunction arises not solely from neuronal injury but from the breakdown of these coordinated interactions. Recent frameworks conceptualize this process as a disturbance of cellular communities, where glial cells actively shape disease progression rather than merely responding to it.A key advance is the recognition that neurodegeneration reflects a failure of metabolic homeostasis, rather than an adaptive “metabolic reprogramming.” Neurons exhibit impaired mitochondrial function and energy utilization, while astrocytes show disrupted metabolic support and neurotransmitter regulation. Microglia adopt states that alter both inflammatory signaling and metabolic balance, contributing to an unstable cellular environment.Critically, these cell-intrinsic changes are accompanied by a breakdown of intercellular metabolic coupling, which normally ensures efficient energy distribution across the brain. Mechanisms such as the astrocyte–neuron lactate shuttle and glutamate–glutamine cycling exemplify how metabolic processes are shared between cell types. In neurodegenerative diseases, disruption of these pathways compromises neuronal function and promotes network instability.This Research Topic aims to bring together studies that elucidate the molecular and cellular mechanisms underlying disrupted metabolic interactions across brain cell types in neurodegenerative diseases, including work using experimental and preclinical models, as well as patient-derived systems. Contributions that identify novel mechanistic pathways or therapeutic targets linked to metabolic dysfunction and neuron–glia interactions are particularly encouraged.Topics of interest include, but are not limited to:• Neuron–glia interactions in neurodegenerative diseases • Metabolic dysfunction and mitochondrial impairment in neurons and glial cells • Astrocyte–neuron metabolic coupling (e.g., lactate shuttle, neurotransmitter cycling) • Microglial activation states and their metabolic and inflammatory roles • Oligodendrocyte support of axonal metabolism and function • Intercellular metabolic coupling and its disruption in disease • Molecular and cellular mechanisms underlying metabolic homeostasis failure • Neurodegeneration as a disorder of cellular network dysfunction • Identification of novel therapeutic targets related to metabolic and glial pathways • Studies using in vivo models, patient-derived systems, and other experimental approaches to investigate neurodegenerative mechanisms Topic editors: Naruhiko Sahara, Tadafumi Hashimoto Source: https://www.frontiersin.org/research-topics/79965/from-neuron-glia-interaction-to-metabolic-coupling-failure-in-neurodegeneration