Nasal Spray Derived From Human Placenta Protects Against Alzheimer's Decline, Study in Mice Shows

The sticky proteins amyloid-beta and tau are hallmark features of Alzheimer's disease, but they're not the only contributors to the condition.

Another factor implicated in cognitive decline is the chronic activation of specific cells in the brain – namely microglia and astrocytes – which can damage neurons through neuroinflammation.

In a new study reported in Translational Neurodegeneration, scientists may have found a way to help counter that inflammation, with help coming from what might seem like an unlikely source: the placenta.

In an experiment, a team led by scientists from the Catholic University of the Sacred Heart in Italy treated mice with a nasal formulation containing tiny particles called extracellular vesicles, derived from cells found in the human placenta.

"A particularly promising avenue within regenerative medicine involves harnessing the therapeutic potential of extracellular vesicles, particularly those isolated from mesenchymal stromal cells (MSCs)," the team writes in their paper, led by first author and cell biologist Andrea Papait.

"MSC-derived EVs (MSC-EVs) are nanoparticles that mediate intercellular communication and have been demonstrated to potentially deliver bioactive molecules with anti-inflammatory and neuroprotective properties."

In their research, the scientists used a particular kind of MSC-derived EV – called human amniotic mesenchymal stromal cell-derived vesicles (hAMSC-EVs) – sourced from the placental amniotic membrane.

Once prepared, the nasal spray formulation was administered to transgenic mice that had been genetically engineered to develop features of Alzheimer's disease.

The mice received doses of the experimental spray twice a week for six months, from three months of age – at which point they hadn't yet manifested Alzheimer's-like symptoms – to nine months of age.

Tests using fluorescent dyes confirmed that the hAMSC-EVs had reached all regions of the hippocampus, and were co-localized with both neurons and microglia.

Behavioral tests showed that mice treated with the hAMSC-EVs formulation exhibited improved cognitive performance compared to control animals in tests measuring object recognition and spatial memory.

The treatment significantly reduced amyloid-beta deposits in the hippocampus, although it didn't seem to affect tau phosphorylation.

Treated animals also showed significantly lowered signs of neuroinflammation in the hippocampus, with reduced activation of both astrocytes and microglia, and they also exhibited higher levels of proteins associated with neuroplasticity, including ARC, GluA1, and BDNF.

In a separate lab experiment, skin cells from people with sporadic Alzheimer's disease were reprogrammed into stem cells and then differentiated into neurons. In these cells, the EV treatment reduced neuronal deterioration and restored healthier levels of expression of proteins related to neuroplasticity.

The results add to previous studies by some of the same team, which suggest that MSCs derived from the placenta have strong immune-modulating properties that may make them well suited for regenerative medicine – including now, possibly, future Alzheimer's treatments.

"Collectively, our findings indicate that hAMSC-EVs attenuate neuroinflammation by reshaping the inflammatory microenvironment rather than through direct immunosuppression," the researchers write.

"The observed changes in microglial phenotype, cytokine profile, and neuroplasticity-related factors suggest that hAMSC-EVs promote a permissive environment that supports neuronal integrity, synaptic function, and the homeostasis of other brain cell populations."

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While there's a huge amount of promise here, the researchers acknowledge we don't know yet whether these positive results would be seen in humans with cognitive decline.

They suggest further studies will be able to investigate the possibility and learn more about the molecular mechanisms that confer these neuroprotective effects.

"These are preclinical results that require further validation in humans and do not yet represent an available therapy for Alzheimer's disease, but they point to a very promising direction," says senior researcher and neuroscientist Claudio Grassi.

"Understanding whether some of the mechanisms through which the placenta naturally regulates inflammation and protects tissues could offer new tools for the treatment of neurodegenerative diseases and, more generally, whether the use of extracellular vesicles represents a new frontier for the treatment of neurological diseases".

The findings are reported in Translational Neurodegeneration.