Human neural stem cell-derived extracellular vesicles mitigate hallmarks of Alzheimer’s disease

Abstract

Background Regenerative 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. Methods Using 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. Results RO 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. Conclusions Collectively, these data demonstrate the neuroprotective effects of systemic administration of stem cell-derived EVs for remediation of behavioral and molecular AD neuropathologies.

News about Therapies of Alzheimer’s Disease: Extracellular Vesicles from Stem Cells Exhibit Advantages Compared to Other Treatments

“…Combinations of this type had been previously hypothesized for BACE-1, however, a few years ago [ 100 ]. At present, the MSC-EVs in various properties [ 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ], in drug delivery [ 91 , 92 ], and in combined employment through a miRNA-BACE-1 axis and various pathways addressed to β-catenin [ 81 , 82 ], have yielded very encouraging results. The new findings concerning MSC-EVs and their therapy agents, considered also in their possible combinations as mentioned here, confirm the improvement of AD therapy, with substantial advantage for the whole population of patients, existing already now and with improvement expected in the next few years.…”

“…Recent results have confirmed the strong potential for MSC-EV as biomarkers for and therapeutic agents against AD [ 83 , 84 , 85 ]. Symptoms observed, including restoration of homeostatic levels, protection of synapses, and improved cognition [ 86 ], are analogous of those of mice. In fact, AD and a number of other diseases are protected by MSC-AVs from neurodegeneration, with positive effects on tissue repair and neural regeneration [ 87 ].…”

Engineering strategies for customizing extracellular vesicle uptake in a therapeutic context

“…[ 5 , 6 ]. For example, MSC-derived EV [ 7 ] and neural stem cell derived EV have been proposed for treatment of osteoarthritis and Alzheimer’s disease, respectively [ 8 ]. Selection of the proper cell source and cell culture method enable researchers to control the amount of EVs produced by donor cells and their properties, which greatly impact EV uptake.…”

Exosomes in Age-Related Cognitive Decline: Mechanistic Insights and Improving Outcomes

“…In APP/PS1 mice across several research groups, the application of exosomes isolated from cultured stem cells (human umbilical, mouse bone barrow, mouse embryonic) can reliably improve performance on cognitive tasks (novel object recognition, Morris Water Maze) and inhibit biological processes associated with cognitive impairment, including the dysregulated expression of pro- and anti-inflammatory cytokines (IL1-β and IL-10), the activation of CNS immune cells (astrocytes, microglia) and the deposition of Aβ (Aβ 1–40 , Aβ 1–42 , plaques) ( Cui et al, 2018 , 2019 ; Ding et al, 2018 ; Wang et al, 2018 ; Li et al, 2020 ; Yang et al, 2020 ). Additional data has suggested such protective effects observed across multiple AD mouse models may be due to the natural inclusion of antioxidants (bioactive catalase) and Aβ degrading enzymes (neprilysin, insulin degrading enzyme) in stem cell exosomes ( de Godoy et al, 2018 ; Ding et al, 2018 ; Lee et al, 2018 ; Bodart-Santos et al, 2019 ; Elia et al, 2019 ; Micci et al, 2019 ; Apodaca et al, 2021 ). Together, these animal studies support the therapeutic potential of engineered exosomes as CNS-specific delivery vehicles to ameliorate cellular and cognitive dysfunction ( Figure 1 ).…”