Abstract
BackgroundRegenerative therapies to mitigate Alzheimer’s disease (AD) neuropathology have shown very limited success. In the recent era, extracellular vesicles (EVs) derived from multipotent and pluripotent stem cells have shown considerable promise for the treatment of dementia and many neurodegenerative conditions.MethodsUsing the 5xFAD accelerated transgenic mouse model of AD, we now show the regenerative potential of human neural stem cell (hNSC)-derived EVs on the neurocognitive and neuropathologic hallmarks in the AD brain. Two- or 6-month-old 5xFAD mice received single or two intra-venous (retro-orbital vein, RO) injections of hNSC-derived EVs, respectively.ResultsRO treatment using hNSC-derived EVs restored fear extinction memory consolidation and reduced anxiety-related behaviors 4–6 weeks post-injection. EV treatment also significantly reduced dense core amyloid-beta plaque accumulation and microglial activation in both age groups. These results correlated with partial restoration of homeostatic levels of circulating pro-inflammatory cytokines in the AD mice. Importantly, EV treatment protected against synaptic loss in the AD brain that paralleled improved cognition. MiRNA analysis of the EV cargo revealed promising candidates targeting neuroinflammation and synaptic function.ConclusionsCollectively, these data demonstrate the neuroprotective effects of systemic administration of stem cell-derived EVs for remediation of behavioral and molecular AD neuropathologies.
Highlights
Regenerative therapies to mitigate Alzheimer’s disease (AD) neuropathology have shown very limited success
In a series of studies, we demonstrated that hippocampal engraftment of human neural stem cell ameliorated neurocognitive and neuroinflammatory effects of a clinically relevant radiation exposure using athymic nude rats [6,7,8,9]
The purified Extracellular vesicle (EV) were diluted into sterile hibernation buffer to deliver 2.25 × 107 EV per 50 μl retro-orbital sinus (RO) injection
Summary
Regenerative therapies to mitigate Alzheimer’s disease (AD) neuropathology have shown very limited success. Similar neuropathologies including persistent inflammation, loss of synaptic integrity, and cognitive impairments have been clearly shown to manifest in the radiation-damaged brain [5]. In a series of studies, we demonstrated that hippocampal engraftment of human neural stem cell (hNSC) ameliorated neurocognitive and neuroinflammatory effects of a clinically relevant radiation exposure using athymic nude rats [6,7,8,9]. These studies showed that stem cell-based approaches improved the functional plasticity of the irradiated host brain, suppressing neuroinflammation, preserving host neuronal morphology, and improving cognitive function. Since significant attrition of engrafted cells was observed, it was hypothesized that the hNSC provided neuroprotective benefits primarily via trophic support rather than proliferation and repopulation [10,11,12]
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