Nanotubular networks in the aging brain: from neuroprotection to neurodegeneration

Intercellular communication in the central nervous system extends far beyond classical synaptic transmission. Contemporary studies utilizing in vivo, super-resolution, and ultrastructural microscopy approaches have revealed dynamic nanotubular networks capable of direct protein, organelle, and Ca²⁺ signal exchange between cells. Microglial tunneling nanotubes (TNTs) support cooperative α-synuclein aggregate clearance and mitochondrial rescue, whereas dendritic nanotubes (DNTs) mediate neuron-to-neuron connectivity that may contribute to amyloid-β redistribution or accumulation before plaque formation. Emerging evidence further suggests that nanotubular functions are dependent on cell type and structure. Microglial TNTs have typically been associated with aggregate handling, clearance, and cellular rescue, whereas neuronal TNTs and recently described DNTs provide distinct examples of disease-relevant cargo redistribution. A central unresolved question is not simply whether nanotubular networks mediate clearance and rescue or facilitate pathological spread, but how their regulation changes during development, adulthood, aging, and neurodegenerative disease. Existing studies emphasize disruption or collapse of TNT and DNT networks as important features of disease progression. Here, we propose that aging may contribute to intermediate states of nanotubular dysfunction before overt collapse, altering the efficiency, directionality, or consequences of intercellular exchange in a cell-type-specific manner. Mapping the cellular and regional dynamics of nanotubular networks in the brain, particularly during aging and Alzheimer's disease, will be essential for determining when nanotubular connectivity supports resilience, becomes dysfunctional, or contributes to pathological protein redistribution. These efforts may reveal therapeutic strategies for preserving nanotubular integrity and function before the development of late-stage neurodegenerative disease.