To evaluate the effects of human amniotic mesenchymal stromal cell-derived extracellular vesicles (hAMSC-EVs) on cognitive performance and neuroinflammation in a preclinical model of Alzheimer's disease.
Approach:
Animal Model: Female triple-transgenic Alzheimer's disease mice received hAMSC-EVs intranasally twice weekly from 3 to 9 months of age.
Cognitive Assessment: Cognitive outcomes were measured using novel object recognition, object place recognition, and Y-maze testing.
Biomarker Evaluation: Hippocampal amyloid-beta levels, tau phosphorylation, glial density and morphology, cytokine profiles, and synaptic protein expression were assessed.
Mechanistic Studies: The microRNA cargo of hAMSC-EVs and their effects on activated microglia and patient-derived neurons were examined.
Key Findings:
Mice treated with hAMSC-EVs had higher preference indices on novel object recognition (63% vs. 55%) and object place recognition (61% vs. 54%) compared to vehicle-treated mice.
Hippocampal amyloid-beta levels were reduced by 53% in treated mice, with concentrations of about 2,744 pg/mg in treated mice vs. 4,713 pg/mg in vehicle-treated mice.
Treatment did not significantly affect tau phosphorylation.
hAMSC-EV treatment reduced neuroinflammation, evidenced by lower microglial and astrocytic density and changes in cytokine profiles.
RNA cargo of hAMSC-EVs contributed to their immunomodulatory effects.
Interpretation:
hAMSC-EVs may have potential effects on cognitive function and neuroinflammation in a preclinical model of Alzheimer's disease.
Limitations:
The study primarily involved female transgenic mice, and treatment began prior to the manifestation of the Alzheimer's disease phenotype.
A shorter treatment course in established phenotype mice did not yield cognitive improvements.
Human experiments were based on neurons from only 6 patients with sporadic Alzheimer's disease and 6 healthy controls.
Conclusion:
Further studies are required to optimize treatment protocols and establish clinical efficacy.
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