Friend or Foe? Glial-Vascular Interactions in Health and Neurodegenerative Disease

Dysfunction of glial and vascular cells is increasingly recognized as a central feature of neurodegenerative diseases. Growing evidence points to disruptions in glial-vascular interactions, which are critical for maintaining the functions of the neurogliovascular unit throughout the lifespan, as key contributors to disease initiation and progression. However, the mechanisms governing this complex intercellular crosstalk and its potential role in disease pathogenesis remain incompletely understood. In this review, we summarize the current understanding of glial—vascular communication across health and disease, with a particular focus on Alzheimer disease, stroke, cerebral small vessel disease, Parkinson disease, Huntington disease, and multiple sclerosis. We highlight emerging cellular and molecular interactions of interest, outline major gaps in our understanding, and discuss innovative tools, including transcriptomics, which are reshaping the study of neurogliovascular dynamics. A central unresolved ques
tion is whether glial and/or vascular dysfunction represents the primary initiating event across neurodegenerative diseases, or whether these processes emerge in parallel through shared upstream drivers. Unraveling these interactions may ultimately reveal novel therapeutic opportunities for a broad range of neurodegenerative conditions.
Significance Statement: Neurogliovascular unit interactions are fundamental to brain homeostasis, yet the molecular basis of this crosstalk and its disruption in neurodegeneration remains poorly understood. This review provides the first comprehensive synthesis of molecular mechanisms governing the Neurogliovascular unit interface across physiological and pathological conditions, integrating evidence from related disorders. By consolidating key signaling pathways, disease-associated alterations, and
emerging experimental approaches, this review offers a unifying framework to guide biomarker development and therapeutic targeting.