Neuroimmune Crosstalk in Neurodegenerative Diseases: Pathogenic Mechanisms and Therapeutic Potential

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis are increasingly understood as disorders of disrupted neuroimmune crosstalk. This review synthesizes recent advances on the bidirectional interactions between CNS glia and peripheral immune cells, emphasizing how dysregulated pathways—including NF-κB, NLRP3 inflammasome, and JAK/STAT signaling—drive chronic inflammation, synaptic dysfunction, and neuronal loss. This study integrates disease-specific mechanisms, from TREM2/CD33 dysfunction in Alzheimer’s to α-synuclein–TLR signaling in Parkinson’s and astrocyte–motor neuron toxicity in ALS. More so, this study highlights how targeting glial phenotypes, immune checkpoints, and the CNS–periphery axis—through CSF1R inhibitors, TREM2 agonists, astrocytic modulators, and microbiota-based strategies—may redefine disease modification. By uniting molecular insights with emerging biomarker-guided interventions, this review under-scores the translational potential of neuroimmune modulation in restoring CNS homeostasis.