BMSCs-exosomes containing GDF-15 alleviated SH-SY5Y cell injury model of Alzheimer's disease via AKT/GSK-3β/β-catenin

Xiong, Wenping; Yao, Weiqi; Wang, Bei; Liu, Kui

doi:10.1016/j.brainresbull.2021.09.008

Cited by 33 publications

(32 citation statements)

References 43 publications

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“…Strategies that can reduce Aβ formation or interrupt their neurotoxicity are badly needed ( Tolar et al, 2020 ). In accordance with previous studies ( Litwiniuk et al, 2020 ; Xiong et al, 2021 ), our results revealed that Aβ was harmful to cells, which was exemplified by the diminution of CCK8 values and increased PI staining compared with those of the normal group. Cumulative evidence has shown that mitochondrial dysfunction is a critical feature in animal models of AD and in patients with AD ( Uddin et al, 2019 ; Chen et al, 2021 ).…”

Section: Discussionsupporting

confidence: 93%

“…AD is an insidiously progressive neurodegenerative disease that occurs primarily in the elderly, with progressive cognitive and behavioral impairment as the main clinical manifestation ( Wang et al, 2021 ). Aβ is one of the hallmarks of AD, and extensive studies have shown that Aβ is toxic to neurons and causes cell death ( Xiong et al, 2021 ; Ju and Tam, 2022 ). Furthermore, multiple lines of evidence have identified Aβ oligomer as crucial cytotoxins associated with AD, as it can damage synaptic function and inhibit long-term potentiation, which is the is the main mechanism responsible for memory decline ( Benilova et al, 2012 ; Tai et al, 2013 ; Yang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

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Exosomes Derived From M2 Microglia Cells Attenuates Neuronal Impairment and Mitochondrial Dysfunction in Alzheimer’s Disease Through the PINK1/Parkin Pathway

Shen

Yang

et al. 2022

Front. Cell. Neurosci.

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The accumulation of abnormal aggregation of amyloid-β plaques is one of the most distinguishing pathologies of Alzheimer’s disease (AD) and is highly toxic to neurons. Exosomes have demonstrated great potential for AD therapy. However, the impact and underlying mechanism of M2 microglia-derived exosomes (M2-EXOs) in AD progression and outcome are seldom explored. Therefore, we employed an Aβ1-42 oligomer (Aβ)-induced AD model in neuronal HT-22 cells and 7-month-old APP/PS1 mice to investigate the effects of M2-EXOs on AD. We revealed that the AD cell model established by Aβ was accompanied by the upregulation of Aβ1-42, neuronal death, alternation of mitochondrial function and autophagy. M2-EXOs can be internalized by HT-22 cells and MAP2-positive neuronal cells in APP/PS1 mice, and exert neuroprotective functions. Specifically, the administration of M2-EXOs in the AD cell model partially increased cell viability, restored the destruction of mitochondrial membrane potential, and reduced the accumulation of reactive oxygen species inside the mitochondria and cells in a dose-dependent manner. Moreover, we demonstrated that PINK1/Parkin mediated mitophagy was enhanced, while incubation with M2-EXOs decreased beclin1, LC3II, PINK1, and Parkin expression levels. Finally, we observed that compared with APP/PS1 mice treated with PBS, the application of M2-EXOs could decrease Aβ plaque deposition and minus Aβ oligomer expression along with improved PINK1/Parkin pathway-mediated autophagy. Overall, our results imply that M2-EXOs play a protective role in the pathogenesis of AD by ameliorating PINK1/Parkin-mediated mitophagy, indicating that it may provide a novel therapeutic strategy to treat AD.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Exosomes Derived From M2 Microglia Cells Attenuates Neuronal Impairment and Mitochondrial Dysfunction in Alzheimer’s Disease Through the PINK1/Parkin Pathway

Shen

Yang

et al. 2022

Front. Cell. Neurosci.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the therapeutic effects of MSC-EVs do not depend only on the whole vesicles. Rather, their released cargo miRNAs induce inhibition of BACE-1 expression and activation of intracellular signaling cascades, such as those operative along the Wnt/β-catenin and the AKT/GSK-3β/β-catenin pathways [ 81 , 82 ]. Therefore, the mechanisms of MSC-EV action appear more complex than previously proposed.…”

Section: Present Therapies For Alzheimer’s Diseasementioning

confidence: 99%

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

Meldolesi

2022

Biomedicines

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Upon its discovery, Alzheimer’s, the neurodegenerative disease that affects many millions of patients in the world, remained without an effective therapy. The first drugs, made available near the end of last century, induced some effects, which remained only marginal. More promising effects are now present, induced by two approaches. Blockers of the enzyme BACE-1 induce, in neurons and glial cells, decreased levels of Aβ, the key peptide of the Alzheimer’s disease. If administered at early AD steps, the BACE-1 blockers preclude further development of the disease. However, they have no effect on established, irreversible lesions. The extracellular vesicles secreted by mesenchymal stem cells induce therapy effects analogous, but more convenient, than the effects of their original cells. After their specific fusion to target cells, the action of these vesicles depends on their ensuing release of cargo molecules, such as proteins and many miRNAs, active primarily on the cell cytoplasm. Operationally, these vesicles exhibit numerous advantages: they exclude, by their accurate selection, the heterogeneity of the original cells; exhibit molecular specificity due to their engineering and drug accumulation; and induce effective actions, mediated by variable concentrations of factors and molecules and by activation of signaling cascades. Their strength is reinforced by their combination with various factors and processes. The recent molecular and operations changes, induced especially by the stem cell target cells, result in encouraging and important improvement of the disease. Their further development is expected in the near future.

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“…found that UCB-MSCs, because of the existence of GDF-15, enhanced Aβ plaque clearance by upregulation of both insulin-degrading enzyme (IDE) and neprilysin expression in microglial cells in vivo, clarifying another therapeutic appliance for AD [ 151 ]. Indeed, GDF-15 improves neprilysin and IDE expression as well as activation by stimulation of AKT/GSK-3β/β-catenin pathway, thus degrading Aβ peptide [ 152 ].…”

Section: Preclinical Studies Based On Msc-derived Exosome Therapy In ...mentioning

confidence: 99%

Therapeutic utility of mesenchymal stromal cell (MSC)-based approaches in chronic neurodegeneration: a glimpse into underlying mechanisms, current status, and prospects

et al. 2022

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Recently, mesenchymal stromal cell (MSC)-based therapy has become an appreciated therapeutic approach in the context of neurodegenerative disease therapy. Accordingly, a myriad of studies in animal models and also some clinical trials have evinced the safety, feasibility, and efficacy of MSC transplantation in neurodegenerative conditions, most importantly in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). The MSC-mediated desired effect is mainly a result of secretion of immunomodulatory factors in association with release of various neurotrophic factors (NTFs), such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Thanks to the secretion of protein-degrading molecules, MSC therapy mainly brings about the degradation of pathogenic protein aggregates, which is a typical appearance of chronic neurodegenerative disease. Such molecules, in turn, diminish neuroinflammation and simultaneously enable neuroprotection, thereby alleviating disease pathological symptoms and leading to cognitive and functional recovery. Also, MSC differentiation into neural-like cells in vivo has partially been evidenced. Herein, we focus on the therapeutic merits of MSCs and also their derivative exosome as an innovative cell-free approach in AD, HD, PD, and ALS conditions. Also, we give a brief glimpse into novel approaches to potentiate MSC-induced therapeutic merits in such disorders, most importantly, administration of preconditioned MSCs.

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BMSCs-exosomes containing GDF-15 alleviated SH-SY5Y cell injury model of Alzheimer's disease via AKT/GSK-3β/β-catenin

Cited by 33 publications

References 43 publications

Exosomes Derived From M2 Microglia Cells Attenuates Neuronal Impairment and Mitochondrial Dysfunction in Alzheimer’s Disease Through the PINK1/Parkin Pathway

Exosomes Derived From M2 Microglia Cells Attenuates Neuronal Impairment and Mitochondrial Dysfunction in Alzheimer’s Disease Through the PINK1/Parkin Pathway

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

Therapeutic utility of mesenchymal stromal cell (MSC)-based approaches in chronic neurodegeneration: a glimpse into underlying mechanisms, current status, and prospects

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