Neuropeptide-GPCR Regulation of the Neuroimmune Axis in Neurodegeneration: Mechanisms and Translation

Chronic neuroinflammation and dysfunction of the neuro-glial-vascular unit (NGVU) are central mechanisms driving the progression of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Neuropeptides, as key regulatory signaling molecules in the central nervous system (CNS), bind to specific G protein-coupled receptors (GPCRs) on the surfaces of microglia, astrocytes, oligodendrocytes, and cerebrovascular elements. Through cell type-specific biased signaling, they precisely regulate the threshold for inflammatory activation, coordinate phagocytosis and autophagy, maintain metabolic homeostasis, and support the function of the blood-brain barrier. This review systematically analyzes the immune-regulatory roles of key neuropeptides, including neuropeptide Y (NPY), vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide (VIP/PACAP), substance P (SP), and calcitonin gene-related peptide (CGRP). We focus on how these systems contribute to CNS homeostasis and disease-relevant processes, including myelin repair and neuroinflammatory regulation. Integrating evidence from preclinical models and human samples, it clarifies the pathological mechanisms linking these neuropeptides to disease progression. The review also outlines a translational research pathway focused on ligand structure engineering, targeted delivery, and biomarker-guided patient stratification, emphasizing receptor subtype selectivity and CNS permeability for precise therapy. By integrating the neuropeptide-mediated neuro-immune network, this work offers new insights into immune pathology in neurodegenerative diseases and provides a foundation for next-generation immune regulation.