Exosomes in Neurodegenerative Diseases: Context-Dependent Molecular Mechanisms and Therapeutic Duality

Exosomes are nanosized extracellular vesicles that mediate intercellular communication in the central nervous system. Over the past decade, accumulating evidence has demonstrated that these vesicles may exert dual and context-dependent effects in neurodegenerative diseases. Under pathological conditions, the exosomes have been found to carry misfolded proteins including amyloid-beta, α-synuclein, and phosphorylated tau – and facilitate their spread between cells, thus exacerbating neurodegeneration. Conversely, increasing evidence indicates that exosomes may also carry neuroprotective cargo such as miR-124, TSG-6, neurotrophic factors, and antioxidant enzymes, which can mitigate oxidative stress, synaptic dysfunction, mitochondrial impairment, and chronic neuroinflammation. Recent progress in stem cell biology and bioengineering has drawn attention to therapeutic potential of exosomes, particularly those isolated from mesenchymal stem cells including those with modified surface or contents. Their ability to cross the blood-brain barrier, being first documented several years ago, along with their capacity to restore neuroglial balance and promote axonal regeneration has led many researchers to consider them promising next-generation therapeutic candidates. Preclinical and early clinical observations suggest that exosome-mediated signaling may actively shape central nervous system (CNS) homeostasis and plasticity, rather than simply being markers of disease states. In this review, we summarize findings from molecular, cellular, preclinical, and translational studies reported over the past decade. Rather than considering exosomes solely biomarkers or drug carriers, we present them as versatile modulators whose functions may be subject to context-dependent shifts, operating at the intersection of pathological and reparative signaling networks. Our analysis covers Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and neurotraumatic conditions, aiming to bridge fundamental exosome biology with clinical applications. We also discuss current challenges and unanswered questions that need to be addressed for successful translation of exosome-based approaches.