ASTROCYTE-DERIVED EXOSOMAL SIGNALLING INDUCES PATHOLOGICAL NEURONAL TRANSCRIPTIONAL RESPONSES IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is characterized by synaptic failure, neuroinflammation, and metabolic dysfunction in addition to amyloid-β and tau pathology. Astrocytes, a type of glial cell, play a vital role in maintaining neuronal homeostasis, partly through the release of astrocyte-derived exosomes (ADEs), yet whether disease-associated changes in ADE cargo directly affect neuronal function remains unclear.
In this study, we investigated whether disease-associated alterations in ADE cargo are sufficient to drive pathological gene expression changes in neurons. ADEs were isolated from the peripheral blood of clinically diagnosed AD patients (n: 5) and age-matched cognitively normal controls (n: 5). Following removal of plasma contaminants, ADE protein cargo was profiled by liquid LC/MS mass spectrometry.
To examine functional effects, primary mouse cortical neurons were exposed to patient derived ADEs for 4 days, followed by transcriptomic analysis of the neurons.
AD-derived ADEs showed loss of metabolic, proteostatic, and cytoskeletal proteins together with enrichment of inflammatory and stress-associated cargo. Neurons exposed to AD ADEs exhibited coordinated transcriptional reprogramming, with suppression of synaptic, mitochondrial, vesicle trafficking, and proteostasis pathways and induction of inflammatory, oxidative stress, and hypoxia-responsive gene programs.
Importantly, pathway-level integration demonstrated relationship between changes in ADE protein cargo and neuronal gene expression. Together, these findings suggest that astrocyte-derived exosomes actively convey disease-associated signals that disrupt neuronal homeostasis and promote vulnerability in Alzheimer’s disease.