2026 Volume 43 Issue 2 Pages 97-103
Neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) have long been viewed primarily as disorders with neuronal loss and pathogenic protein aggregation. Over the past two decades, however, glial cells–especially microglia and astrocytes–have emerged as active drivers and modulators of disease progression. In parallel, advances in single–cell and single–nucleus transcriptomics have revealed remarkable heterogeneity of neuroinflammatory states, reshaping our understanding of disease mechanisms. In this review, we first summarize the current concepts of neuroinflammation and microglial activation, including the limitations of the classical M1/M2 framework and the concept of non–cell autonomous neurodegeneration driven by neuron–glia–immune cell interactions. We then focus on disease–associated microglia, highlighting shared “neurodegeneration-associated” gene programs across AD and ALS, as well as the loss of homeostatic microglial signatures in human postmortem brains. We further discuss astrocyte pathology including disease–associated astrocytes and dysregulation of astrocyte morphological complexity and homeostatic functions, which interact with microglial responses to shape synaptic integrity and neuronal survival. Next, we review the bidirectional crosstalk between microglia and peripheral immune cells. In AD and tauopathies, infiltrating T cells–particularly cytotoxic T cells–can exacerbate neurodegeneration, whereas in ALS certain CD4+ T cell subsets and regulatory T cells appear to promote neuroprotective microglial phenotypes. Finally, we discuss therapeutic strategies targeting microglia and the broader neuroimmune network, including approaches to enhance beneficial DAM/MGnD–like responses or dampen maladaptive inflammatory signaling, as well as ongoing clinical trials of glia–modulating agents and T cell–directed therapies. Future disease–modifying therapies will need to precisely reprogram glial and immune states within spatially and temporally dynamic neuroinflammatory networks in AD, ALS, and related disorders.
