Tho Quang Trinh

Background:  Alzheimer’s disease (AD) is the most common form of dementia, characterized by progressive memory loss, language, and cognitive function.¹ Pathologically, AD is marked by the accumulation of amyloid-beta (Aβ) plaques, tau hyperphosphorylation leading to neurofibrillary tangles, chronic neuroinflammation, and synaptic degeneration.¹ Current treatments for AD provide only symptomatic relief and do not stop disease progression.  Lately, mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) emerged as a promising therapeutic option due to their ability to modulate neuroinflammation, reduce Aβ and tau pathology, and enhance neuroregeneration.²    

Objective:  In this narrative review, we examined how MSCs and MSC-EVs modulate AD pathology in preclinical models.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2025 using the following keywords: “MSC”, “EVs, ” Alzheimer”.

Results:  MSCs have been shown to reduce hyperphosphorylated tau levels in a preclinical model of AD. In 3xTg-AD female mice, tau expression and phosphorylation were evaluated following intravenous MSC administration.³ In G2 (early long-term treatment), mice received four bi-monthly injections starting at 5 months and were analyzed at 12 months, showing a 24% reduction in cortical tau levels compared to controls. In G3 (late short-term treatment), mice received four bi-weekly injections starting at 10 months and were analyzed at 12 months, showing a slight increase in tau levels after treatment.³ In addition to tau modulation, MSCs have been found to help restore neuronal integrity. Using an LPS-induced neuroinflammation model, researchers observed preservation of α7 nicotinic acetylcholine receptor (α7 nAChR) levels, which are vital for neuronal survival and anti-apoptotic signaling.⁴ MSCs also stabilized mitochondrial function by limiting cytochrome c release, effectively preventing and reversing both receptor loss and mitochondrial dysfunction.⁴ Cognitive improvements have also been linked to MSC treatment. In behavioral testing using the Novel Object Recognition task, LPS-treated mice displayed significant memory impairment. ⁴ Treatment with either mouse or human MSCs reversed this deficit, restoring recognition memory to near-normal levels. ⁴ Beyond cognitive effects, MSCs appear to attenuate Aβ plaque deposition. In an LPS-induced AD-like model, MSC therapy prevented amyloid buildup and reduced deposits in the frontal cortex, striatum, and hippocampus. ⁴ Similarly, in an Aβ-induced rat model of AD, MSCs lowered plaque levels, possibly through modulation of the lncRNA TUSC7/miR-449a/PPARγ signaling pathway. ⁵ Their impact on neuroinflammation was also well-documented in the research articles. A single MSC injection in 3xTg-AD mice reduced early markers of inflammation, such as GFAP and Iba1.³ Repeated dosing further enhanced neuronal health by increasing TUJ1 expression in the hippocampus, suggesting a dual role in mitigating inflammation and promoting neuroprotection.³ Emerging data on MSC-EVs further support their therapeutic potential. In a streptozotocin (STZ)-induced model of AD, treatment with bone marrow-derived MSC-EVs significantly improved recognition memory, though spatial memory and depressive-like behaviors were unaffected.² These EVs have also shown promise in reducing tau and amyloid pathology. In the same STZ model, MSC-EVs led to a marked decline in phosphorylated tau levels, indicating efficacy in targeting tau-related neurodegeneration through both central and peripheral mechanisms.² Anti-inflammatory effects have likewise been observed with MSC-EVs. In SH-SY5Y neuronal cultures co-cultured with LPS-activated BV-2 microglia and exposed to Aβ, MSC-EVs suppressed inflammation by lowering M1 microglial markers and nitric oxide production.¹ Furthermore, in STZ-injected mice, these EVs diminished hippocampal neuroinflammation by reducing microglial activation and associated inflammatory markers.²

Conclusion:  MSCs and MSC-EVs exert therapeutic effects in AD by modulating microglia, suppressing inflammatory signals, and promoting the clearance of Aβ plaques and hyperphosphorylated tau, thereby contributing to the restoration of memory, neuron health, and brain function. MSC-EVs offer a safer, cell-free alternative to MSC therapy, but treatment conditions may require optimization to achieve maximal therapeutic efficacy and require repeated dosing.

Works Cited:

1. Zavatti M, Gatti M, Beretti F, Palumbo C, Maraldi T. Exosomes Derived from Human Amniotic Fluid Mesenchymal Stem Cells Preserve Microglia and Neuron Cells from Aβ. Int J Mol Sci. 2022;23(9):4967. Published 2022 Apr 29. doi:10.3390/ijms23094967
2. Liu S, Fan M, Xu JX, et al. Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology. J Neuroinflammation. 2022;19(1):35. Published 2022 Feb 7. doi:10.1186/s12974-022-02393-2
3. Neves AF, Camargo C, Premer C, Hare JM, Baumel BS, Pinto M. Intravenous administration of mesenchymal stem cells reduces Tau phosphorylation and inflammation in the 3xTg-AD mouse model of Alzheimer’s disease. Exp Neurol. 2021;341:113706. doi:10.1016/j.expneurol.2021.113706
4. Lykhmus O, Koval L, Voytenko L, et al. Intravenously Injected Mesenchymal Stem Cells Penetrate the Brain and Treat Inflammation-Induced Brain Damage and Memory Impairment in Mice. Front Pharmacol. 2019;10:355. Published 2019 Apr 17. doi:10.3389/fphar.2019.00355
5. Pezeshki SP, Karimi Darabi M, Nazeri Z, et al. Mesenchymal Stem Cells Therapy Led to the Improvement of Spatial Memory in Rats with Alzheimer’s disease Through Changing the Expression of LncRNA TUSC7/ miR-449a/ PPARγ and CD36 Genes in the Brain Tissue. Int J Mol Cell Med. 2023;12(2):108-119. doi:10.22088/IJMCM.BUMS.12.2.108