Intravenous administration of mesenchymal stem cells reduces Tau phosphorylation and inflammation in the 3xTg-AD mouse model of Alzheimer's disease

Neves, Amanda Ferreira; Camargo, Christian; Premer, Courtney; Hare, Joshua M.; Baumel, Bernard; Pinto, Milena

doi:10.1016/j.expneurol.2021.113706

Cited by 39 publications

(38 citation statements)

References 68 publications

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“…The effects on BDNF, NeuN, GFAP, Iba-1, and NEP were significantly more prominent in the NEP-enhanced hUC-MSC group than in the naïve group; this resulted from the increased amount of NEP in the hippocampus from enriched NEP-possessing EVs. It has been reported that MSCs of various origins, such as the adipose, bone marrow, placenta, and umbilical cord blood, affect functional recovery in AD animal models [58]. Additionally, it has been reported that umbilical cordderived MSCs improve cognitive function in a transgenic mouse model [12,24,59].…”

Section: Discussionmentioning

confidence: 99%

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Extracellular Vesicles Released from Neprilysin Gene-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cell Enhance Therapeutic Effects in an Alzheimer’s Disease Animal Model

Jeong

Kim

et al. 2021

Stem Cells International

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Alzheimer’s disease (AD) animal studies have reported that mesenchymal stem cells (MSCs) have therapeutic effects; however, clinical trial results are controversial. Neprilysin (NEP) is the main cleavage enzyme of β-amyloid (Aβ), which plays a major role in the pathology and etiology of AD. We evaluated whether transplantation of MSCs with NEP gene modification enhances the therapeutic effects in an AD animal model and then investigated these pathomechanisms. We manufactured NEP gene-enhanced human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and intravenously transplanted them in Aβ1-42-injected AD animal models. We compared the differences in behavioral tests and immunohistochemical assays between four groups: normal, Aβ1-42 injection, naïve hUC-MSCs, and NEP-enhanced hUC-MSCs. Both naïve and NEP-enhanced hUC-MSC groups showed significant improvements in memory compared to the Aβ1-42 injection group. There was no significant difference between naïve and NEP-enhanced hUC-MSC groups. There was a significant decrease in Congo red, BACE-1, GFAP, and Iba-1 and a significant increase in BDNF, NeuN, and NEP in both hUC-MSC groups compared to the Aβ1-42 injection group. Among them, BDNF, NeuN, GFAP, Iba-1, and NEP showed more significant changes in the NEP-enhanced hUC-MSC group than in the naïve group. After stem cell injection, stem cells were not found. Extracellular vesicles (EVs) were equally observed in the hippocampus in the naïve and NEP-enhanced hUC-MSC groups. However, the EVs of NEP-enhanced hUC-MSCs contained higher amounts of NEP as compared to the EVs of naïve hUC-MSCs. Thus, hUC-MSCs affect AD animal models through stem cell-released EVs. Although there was no significant difference in cognitive function between the hUC-MSC groups, NEP-enhanced hUC-MSCs had superior neurogenesis and anti-inflammation properties compared to naïve hUC-MSCs due to increased NEP in the hippocampus by enriched NEP-possessing EVs. NEP gene-modified MSCs that release an increased amount of NEP within EVs may be a promising therapeutic option in AD treatment.

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Section: Discussionmentioning

confidence: 99%

“…Therefore, we selected hUC-MSCs as a source of stem cell treatment for AD. As intraparenchymal injection of stem cells is considered high-risk [60] and intra-arterial injection of stem cells causes microembolism [61], we intravenously administered hUC-MSCs [58] to decrease these possible side effects.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Vesicles Released from Neprilysin Gene-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cell Enhance Therapeutic Effects in an Alzheimer’s Disease Animal Model

Jeong

Kim

et al. 2021

Stem Cells International

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“…BM-MSCs have also been reported to secrete the anti-inflammatory microRNA miR-146a, which, when taken up by astrocytes in the hippocampi of APP/PS1 mice, resulted in decreased gliosis and pro-inflammatory cytokine expression. In another study, multiple BM-MSC intravenous injections in 3xTg-AD mice, in addition to attenuating neuroinflammation and inhibiting β-secretase activity, significantly reduced total and phosphorylated tau burden (112). Finally, in a study on 5xFAD mice that aimed to determine the optimal location for BM-MSC brain implantation, comparison of transplantation into the lateral ventricles, the hippocampus, and into both of these regions showed the greatest effectiveness in the case of lateral ventricle injection (113).…”

Section: Mesenchymal and Hematopoietic Stem Cellsmentioning

confidence: 97%

Advances in stem cell therapy in Alzheimer’s disease: a comprehensive clinical trial review

Stefanou¹,

Bennett²,

Politis³

et al. 2022

Stem Cell Investig

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Alzheimer's disease (AD) is the most common type of dementia responsible for more than 121,499 deaths from AD in 2019 making AD the sixth-leading cause in the United States. AD is a progressive neurodegenerative disorder characterized by decline of memory, behavioral impairments that affects a person's ability to function independently ultimately leading to death. The current pressing need for a treatment for (AD) and advances in the field of cell therapy, has rendered stem cell therapeutics a promising field of research. Despite advancements in stem cell technology, confirmed by encouraging preclinical utilization of stem cells in AD animal models, the number of clinical trials evaluating the efficacy of stem cell therapy is limited, with the results of many ongoing clinical trials on cell therapy for AD still pending. Mesenchymal stem cells (MSCs) have been the main focus in these studies, reporting encouraging results concerning safety profile, however their efficacy remains unproven. In the current article we review the latest advances regarding different sources of stem cell therapy and present a comprehensive list of every available clinical trial in national and international registries. Finally, we discuss drawbacks arising from AD pathology and technical limitations that hinder the transition of stem cell technology from bench to bedside.Our findings emphasize the need to increase clinical trials towards uncovering the mode of action and the underlying therapeutic mechanisms of transplanted cells as well as the molecular mechanisms controlling regeneration and neuronal microenvironment.

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“…showed anti-inflammatory effects, promoted Aβ cleavage and decreased phospho-tau level. 96 Repetitive intranasal delivery of human NSCs (8 μl, 1 × 10 6 cells, 4 μl/side) also exhibited widespread neuroprotective effects against AD. 97 Moreover, neural crest-derived nasal turbinate stem cells (NTSCs), 98 bone marrow mesenchymal stem cells (BM-MSCs), 99,100 umbilical cord-derived mesenchymal stem cells (hUC-MSCs), 101 human induced pluripotent stem cell (hiPSCs) 102,103 etc.…”

Section: Cell Transplantationmentioning

confidence: 99%

Hippocampal neurogenesis and pro‐neurogenic therapies for Alzheimer's disease

Zheng

2022

Anim Models and Exp Med

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Adult hippocampal neurogenesis (AHN) in the hippocampal dentate gyrus (DG) subset enables the neuronal network to encode new information flexibly and update stored content in due time. 1 Though the number of adult-born neurons declines with age, there is increasing evidence of an indispensable role for limited AHN in hippocampusdependent learning, memory and emotional regulation. 2Alzheimer's disease (AD) is the most common cause of dementia in people over age 65. It is characterized by progressive neurodegeneration in the brain, with no treatment to date for halting disease progression. A sea of money has been invested in the development of anti-AD drugs. Two major drug targets include the extracellular amyloid-beta (Aβ) protein and intraneuronal hyperphosphorylated tau. Besides considering the anti-neurodegenerative potential of AHN and other pro-neurogenic treatments, neuroscientists are also trying to develop new drugs to directly facilitate neurogenesis in the AD brain. 3 However, introducing neurogenesis is challenging in AD. The pool of active hippocampal neural stem cells (NSCs) is prone to being progressively depleted due to sustained homeostatic abnormality within the neurogenic niche under AD and accelerated aging. 4 Innate AHN is dysregulated under AD and the underlying mechanisms remain largely unknown, 5 which hinders the development of pro-AHN drugs. Simultaneously, emerging techniques such as cell transplantation and glia-neuron reprogramming also shed new light on the proneurogenic treatment of AD. 3 These strategies may help overcome

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Intravenous administration of mesenchymal stem cells reduces Tau phosphorylation and inflammation in the 3xTg-AD mouse model of Alzheimer's disease

Cited by 39 publications

References 68 publications

Extracellular Vesicles Released from Neprilysin Gene-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cell Enhance Therapeutic Effects in an Alzheimer’s Disease Animal Model

Extracellular Vesicles Released from Neprilysin Gene-Modified Human Umbilical Cord-Derived Mesenchymal Stem Cell Enhance Therapeutic Effects in an Alzheimer’s Disease Animal Model

Advances in stem cell therapy in Alzheimer’s disease: a comprehensive clinical trial review

Hippocampal neurogenesis and pro‐neurogenic therapies for Alzheimer's disease

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