Galectins as stress-integrating regulators of neuroimmune signaling and proteinopathy in the central nervous system

Galectins are β-galactoside-binding lectins that play increasingly mechanistic functions in central nervous system (CNS) physiology and disease. Over the past decade, a rapidly expanding literature has identified galectins as regulators of microglial activation, misfolded protein pathology, vesicle damage sensing, autophagy, synaptic plasticity, myelination, vascular repair, and neuroimmune communication. Galectins operate across intracellular and extracellular compartments to integrate cellular stress and innate immune signaling. Here, we review CNS studies of galectin-1, galectin-3, galectin-4, galectin-8, and galectin-9, focusing primarily on work published from 2019 onward while incorporating selected earlier studies to establish foundational concepts. Across experimental models and human studies, galectins orchestrate microglial state transitions, regulate aggregation and propagation of amyloid-β, tau, α-synuclein, and mutant huntingtin, and function as intracellular sensors of vesicle and lysosomal damage. Multiple studies further establish galectins as biomarkers and therapeutic targets across Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, stroke, traumatic brain injury, spinal cord injury, retinal degeneration, and chronic pain. Importantly, this review highlights a stage- and context-dependent paradox in which the same galectin axis can amplify neuroinflammation and proteopathic spread in some settings yet support recovery or tissue protection in others. Together, these findings position galectins as central regulators that convert intracellular stress into coordinated neuroimmune programs shaping proteinopathy, circuit dysfunction, and tissue remodeling.