Alzheimer’s disease (AD), a neurodegenerative disease, is the leading cause of dementia worldwide (1).  Although the pathophysiology of AD is diverse, it is mainly characterized by hyperphosphorylation of tau protein, accumulation of beta-amyloid peptide (Aβ), presence of activated microglia, and mass neuronal and synaptic loss (2). The activated microglia secrete cytokines including TNF-α and IL-1β which further exacerbate neuroinflammation. All of these events can cause neuronal death that, over time, can progressively cause memory loss and cognitive decline. Currently, there is no therapy available for AD that can reverse the damage or cure the disease (2). However, since AD is a neurodegenerative disease, stem cell therapy is potentially of great interest.  Mesenchymal stem cells (MSCs) are most commonly studied stem cells due their accessibility and ease of handling. Because transplanted MSCs in rodents have been shown to successfully differentiate in neuronal cells, increase the levels of acetylcholine neurotransmitters, BDNF and NGF, and improve cognitive function, they can potentially be used for AD treatment (2). 

Animal studies on AD suggest that MSC transplantation can reduce Aβ deposition and neuronal death, stimulate neurogenesis and neuronal differentiation, and rescue memory deficits. Further, MSCs have shown to upregulate anti-inflammatory cytokines such as IL-10 and downregulate pro-inflammatory cytokines TNF-α and IL-1β (2). The pro-inflammatory cytokines intensify neuroinflammation, which is a hallmark of AD pathogenesis. However, beneficial effects of MSC are attributed to cell secretion rather than migration of cells to the target site. Several studies investigating the distribution of MSCs after system infusion projected that localization of stem cells at target tissue is rare (3); accumulating evidence indicates that MSCs- derived extracellular vesicles (EVs) are key mediators of the therapeutic efficacy of MSCs. Moreover, these relatively small sized (50–150 nm in diameter) vesicles have potential to transport to a longer distance as compared to stem cells and can cross the blood brain barrier easily (3). 

MSC-EVs have potential to regulate neuroinflammation, a central pathological process in AD, by inhibiting the proliferation and differentiation of lymphocytes. In addition, MSC-EVs can reduce the potential of T cells to differentiate into interleukin 17-producing effector T cells (Th17) (4). Further, the extracellular vesicles can inhibit the activation of microglia and cytokine production. The accumulation of Aβ induces the expression of nitric oxide synthase (NOS) in glial cells, which then can release high levels of nitric oxide (NO). NO induces neurotoxicity, which causes neuronal death, mainly by inhibiting the mitochondrial respiration (4).  Additionally, human MSC-EVs have shown to protect hippocampal neurons by inhibiting oxidative stress and synapse damage. The presence of endogenous active antioxidant enzyme, catalase, has been projected to be a key component of neuroprotection provided by MSC-EVs (4). The neuroprotection provided by MSC-EVs can prevent AD from developing, thereby inhibiting memory loss and cognitive decline. 

MSCs can be genetically modified to further enhance the therapeutic efficacy of EVs for treating AD by reducing the Aβ level in the brain. The production of β-amyloid is the result of proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretases. The synthesis and degradation of Aβ is critically regulated, however, if clearance capacity of lysosomes and glial cells is overloaded then Aβ is released into extracellular space and transmitted to different brain areas (3). The clearance of the pathologic protein can be a promising treatment of AD. Neprilysin (NEP), insulin- degrading enzyme (IDE), and zinc metallopeptidases are capable of degrading Aβ in the brain (3). The overexpression of NEP and IDE has been shown to significantly reduce Aβ plaques of AD transgenic mice (3). The overproduction of Aβ can have pathological consequences, therefore, siRNA knockdown or inhibition of proteins involved in the synthesis of Aβ (β- secretase and γ-secretase) are also areas of interest for potential treatment. MSC-EVs can be used to deliver either siRNA or inhibitors of the protein to the brain, which will inhibit Aβ build up and plaque formation in the brain. Previous animal study showed that the delivery of β-site APP-cleaving enzyme 1 (BACE-1) siRNA, which targets β- secretase led to 55% reduction in the levels of Aβ (5). 

The therapeutic potential of MSC-EVs in the treatment of AD has not been tested clinically. However, their beneficial effects have been observed in chronic kidney disease and stroke. In phase II/III clinical trial, MSC-EVs reduced inflammation and improved kidney function in the patients with chronic kidney disease (4). Similarly, MSC-EVs improved brain edema, deteriorating stroke, stroke recurrences, and hemorrhagic transformation in stroke patients (4).

MSC-EVs are anti-inflammatory, minimal immunogenicity, and have low risk of tumor formation. Unlike stem cells, EVs cannot replicate, therefore there is no risk of uncontrolled division and tumor formation. Further, there is no risk of mutations and DNA damage as associated with cell transplantation. Additionally, the surface of MSC-EV can be modified to make it more specific to target cell type. However, MSC-EVs still have to overcome great challenges before it can be used as a therapeutic agent. The isolation, storage, and purification methods have to be standardized to enhance the reproducibility and comparability

1.     Dementia. Accessed 28 February, 2021.

2.     Duncan T, Valenzuela M. Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther. 05 2017;8(1):111. doi:10.1186/s13287-017-0567-5

3.     Liew LC, Katsuda T, Gailhouste L, Nakagama H, Ochiya T. Mesenchymal stem cell-derived extracellular vesicles: a glimmer of hope in treating Alzheimer’s disease. Int Immunol. 01 2017;29(1):11-19. doi:10.1093/intimm/dxx002

4.     Guo M, Yin Z, Chen F, Lei P. Mesenchymal stem cell-derived exosome: a promising alternative in the therapy of Alzheimer’s disease. Alzheimers Res Ther. 09 2020;12(1):109. doi:10.1186/s13195-020-00670-x

5.  Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. Apr 2011;29(4):341-5. doi:10.1038/nbt.1807