Lucas Lott

Background: As life expectancy continues to rise globally, the increase in population aging has reflected a similar increase in neurological diseases (NDs), such as Alzheimer’s disease (AD)¹. AD is categorized as a decline in memory, cognition, awareness, and motor functionality as a result of the accumulation of amyloid-beta (Aβ) plaques, release of inflammatory cytokines, and overexpression of pro-apoptotic factors². Treatment options include neuroprotective macromolecules, targeted drug delivery systems, and mesenchymal stem cells (MSCs), however, these treatments only serve to improve quality and/or length of life but cannot reverse the damage incurred³. MSC-EVs are poised to offer significantly better biocompatibility and immunogenicity, reducing oxidative stress, neuroinflammation, neurodegeneration, Aβ plaque, and Tau aggregation³.

Objective: Through this narrative review, we explored the promising research detailing the mechanisms by which (miR)-29c-3p, contained within MSC-EVs, reduces neurodegeneration and stimulates neuroprotective factors.

Search Methods: An online search in PubMed was conducted from 2018 to 2023 using the following keywords: “Alzheimer’s”, ” Exosomes”, “Amyloid”, ” transcriptional regulators”.

Results: MSC-EVs have been shown to carry miRNAs and other regulatory molecules that can target and downregulate BACE1 (β-site amyloid precursor protein cleaving enzyme 1) expression in recipients like neurons and glial cells². This activates Wnt, which stabilizes β-catenin enough to accumulate within the cytoplasm, allowing it to translocate into the nucleus for blood brain barrier effects and anti inflammatory cytokines (IL-1β, IL-6, and TNF-α)^2,4. Elevated of pro-apoptotic factors were also reduced through miR-29c expression by downregulating Puma, Hrk, Bmf, N-Bak, and Bim⁴. Bim is a BH3 class molecule that promotes apoptosis by binding to and neutralizing anti-apoptotic Bcl-2 proteins, thus freeing Bax to bind to Bak; this subsequently alters the mitochondrial outer membrane permeabilization, allowing VDAC1 channels to form and leak cytochrome c into the cytoplasm^4,5. Lastly, cyt c completes the formation of apoptosomes that activate executioner caspase-3 for cell death⁴. Stimulating the production of tight junction proteins Claudin-5, zonula occludins-1, and glucose transporter Glut-1 in the brain endothelial cells was achieved with   Wnt3a activation, stabilizing LRP6, and leading to an accumulation of nuclear β-catenin that acts as a transcriptional co-activator for these blood brain barrier proteins junctional proteins⁶. Importantly, a phase II clinical trial showed that MSC-EVs have significant therapeutic effects on AD patients, wherein bi-weekly administration of MSC-EVs intranasally were tolerated and appeared safe⁷. With treatment, two different cognitive metrics were used: the Alzheimer’s Disease Assessment Scale (ADAS) scores decreased by 2.3 points and the Montreal Cognitive Assessment scores increased by 2.4 points at week 12 compared with baseline levels, indicating improved cognitive function⁷. By 36 weeks, ADAS scores decreased nearly 4 points⁷.

Conclusions: BM-MSC-EVs release (miR)-29c-3p inside neuronal cells, inhibiting the BACE1 gene which activates the Wnt/β-catenin pathway. This effectively lowers levels of Aβ1-42 and inflammatory cytokine (IL-1β, IL-6, and TNF-α) through M2 microglial stimulation. Extracellular Aβ-induced pathologies can be repaired by targeting the LRP6 regulator, activating the Wnt/β-catenin pathway in BECs and subsequently increasing their tight junction integrity.

Works Cited:

1. Yin T, Liu Y, Ji W, et al. Engineered mesenchymal stem cell-derived extracellular vesicles: A state-of-the-art multifunctional weapon against Alzheimer’s disease. Theranostics. 2023;13(4):1264-1285. Published 2023 Feb 5. doi:10.7150/thno.81860.
2. Sha S, Shen X, Cao Y, Qu L. Mesenchymal stem cells-derived extracellular vesicles ameliorate Alzheimer’s disease in rat models via the microRNA-29c-3p/BACE1 axis and the Wnt/β-catenin pathway. Aging (Albany NY). 2021;13(11):15285-15306. doi:10.18632/aging.203088.
3. Bang OY, Kim JE. Stem cell-derived extracellular vesicle therapy for acute brain insults and neurodegenerative diseases [published correction appears in BMB Rep. 2022 Apr;55(4):204]. BMB Rep. 2022;55(1):20-29.
4. Yavar J, Hamideh M, Arman M, et al. Therapeutic Effects of Transplanted Exosomes Containing miR-29b to a Rat Model of Alzheimer’s Disease. Frontiers in Neuroscience. 2020; 14. doi:10.3389/fnins.2020.00564.
5. Ding, M., Shen, Y., Wang, P. et al. Exosomes Isolated From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer’s Disease. Neurochem Res. 2018; 43:2165-2177. doi.org/10.1007/s11064-018-2641-5.
6. Qi Wang, Xiaomin Huang, Yixun Su, Guowei Yin, et al. Activation of Wnt/β-catenin pathway mitigates blood–brain barrier dysfunction in Alzheimer’s disease, Brain. 2022; 145(11):4474-4488. doi.org/10.1093/brain/awac236.
7. Xie X, Song Q, Dai C, et al. Clinical safety and efficacy of allogenic human adipose mesenchymal stromal cells-derived exosomes in patients with mild to moderate Alzheimer’s disease: a phase I/II clinical trial. General Psychiatry. 2023; 36:e101143. doi:10.1136/gpsych-2023-101143.