Extracellular vesicles derived from human amniotic mesenchymal stromal cells may improve cognitive performance and reduce amyloid-beta accumulation and neuroinflammation in preclinical trials of Alzheimer's disease.
Researchers evaluated human amniotic mesenchymal stromal cell–derived extracellular vesicles (hAMSC-EV) in female triple-transgenic Alzheimer's disease mice. The vesicles were administered intranasally twice weekly from 3 to 9 months of age, beginning prior to the development of the Alzheimer's disease phenotype. The researchers studied glutamatergic neurons differentiated from induced pluripotent stem cells obtained from 3 patients with sporadic Alzheimer's disease and 3 healthy controls.
Cognitive outcomes were assessed using novel object recognition, object place recognition, and Y-maze testing. The researchers evaluated hippocampal amyloid-beta levels, tau phosphorylation, glial density and morphology, cytokine profiles, and synaptic protein expression. Additional experiments examined the microRNA cargo of the hAMSC-EVs and their effects on activated microglia and patient-derived neurons.
After 6 months of treatment, mice receiving hAMSC-EVs had higher preference indices compared with vehicle-treated mice on novel object (63% vs. 55%) and object place (61% vs. 54%) recognition as well as Y-maze spontaneous alternation (63% vs. 55%). The researchers found fluorescently labeled hAMSC-EVs throughout the hippocampus, where they colocalized with neurons and microglia.
Hippocampal amyloid-beta was reduced by 53% with hAMSC-EVs, and amyloid-beta–1–42 concentrations were about 2,744 pg/mg in treated mice vs. 4,713 pg/mg in vehicle-treated mice. However, treatment did not significantly affect tau phosphorylation, indicating that its effects did not extend across both major Alzheimer's disease–related protein pathologies.
Additionally, hAMSC-EV treatment reduced hippocampal neuroinflammation. The researchers observed lower microglial and astrocytic density, structural remodeling of microglia, and changes in the local cytokine profile, with reductions in proinflammatory cytokines and increases in anti-inflammatory cytokines. Expression of neuroplasticity-related proteins increased.
Mechanistic experiments indicated that RNA cargo contributed to the immunomodulatory effects. In lipopolysaccharide-activated microglia, pretreatment with hAMSC-EVs reduced amyloid-beta uptake by 52% and reactive polynucleated cells by 56%. When the researchers depleted much of the RNA cargo, the vesicles lost their ability to attenuate lipopolysaccharide-dependent microglial activation. The depleted cargo included inflammation-related microRNAs, supporting an RNA-dependent mechanism.
In the human cellular model, hAMSC-EVs prevented neurite atrophy in glutamatergic neurons derived from patients with sporadic Alzheimer's disease and restored several synaptic proteins without affecting cell viability. The researchers revealed complementary evidence of effects on neuronal integrity, but they were conducted in vitro.
The study had several limitations. The primary in vivo experiments involved only female transgenic mice with treatment that began prior to manifestation of the Alzheimer's disease phenotype. When treatment was initiated in mice with an established phenotype, a shorter 1-month course did not improve object place recognition. The human experiments involved neurons derived from just 6 patients with and without Alzheimer's disease and therefore did not establish clinical efficacy.
“Although preliminary evidence suggests that hAMSC-EVs may also attenuate cognitive decline at advanced stages of disease, further studies are required to optimize treatment protocols,” wrote lead study author Andrea Papait, of Università Cattolica del Sacro Cuore in Italy, and colleagues.
The study authors reported no conflicts of interest.
Source: Translational Neurodegeneration
