Research progress in animal models and stem cell therapy for Alzheimer&amp;rsquo;s disease

Han, Fabin; Wang, Wei; Chen, Chao

doi:10.2147/jn.s74160

Cited by 7 publications

(10 citation statements)

References 98 publications

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“…Human brain evolutive changes prevent AD-model animals from fully emulating human LOAD. This hampers any successful translation of pharmacological results reaped from AD-model animals to human clinical settings (Cummings et al, 2014 ; Han et al, 2015 ). Astrocytes' roles in AD progression deserve a careful consideration.…”

Section: Interactions Between Neurons and Astrocytes In Loadmentioning

confidence: 99%

“…Conversely, in most Tg rodents AD-models neurons are spared whereas astrocytes undergo an earlier cytotoxic injury and death. That's why any drug reportedly “successful” in AD-model animals has failed the test of clinical trials (reviewed in Han et al, 2015 ); and (iii) most previous clinical trials of candidate anti-AD drugs recruited patients already at the symptomatic stage of EOFAD or LOAD, viz . their cognitive cortical areas had already undergone irretrievable damage (Cummings et al, 2014 ).…”

Section: Alzheimer's Disease (Ad): An Introductionmentioning

confidence: 99%

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Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease

et al. 2016

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In aged subjects, late-onset Alzheimer's disease (LOAD) starts in the lateral entorhinal allocortex where a failure of clearance mechanisms triggers an accumulation of neurotoxic amyloid-β42 oligomers (Aβ42-os). In neurons and astrocytes, Aβ42-os enhance the transcription of Aβ precursor protein (APP) and β-secretase/BACE1 genes. Thus, by acting together with γ-secretase, the surpluses of APP and BACE1 amplify the endogenous production of Aβ42-os which pile up, damage mitochondria, and are oversecreted. At the plasmalemma, exogenous Aβ42-os bind neurons' and astrocytes' calcium-sensing receptors (CaSRs) activating a set of intracellular signaling pathways which upkeep Aβ42-os intracellular accumulation and oversecretion by hindering Aβ42-os proteolysis. In addition, Aβ42-os accumulating in the extracellular milieu spread and reach mounting numbers of adjacent and remoter teams of neurons and astrocytes which in turn are recruited, again via Aβ42-os•CaSR-governed mechanisms, to produce and release additional Aβ42-os amounts. This relentless self-sustaining mechanism drives AD progression toward upper cortical areas. Later on accumulating Aβ42-os elicit the advent of hyperphosphorylated (p)-Tau oligomers which acting together with Aβ42-os and other glial neurotoxins cooperatively destroy wider and wider cognition-related cortical areas. In parallel, Aβ42-os•CaSR signals also elicit an excess production and secretion of nitric oxide and vascular endothelial growth factor-A from astrocytes, of Aβ42-os and myelin basic protein from oligodendrocytes, and of proinflammatory cytokines, nitric oxide and (likely) Aβ42-os from microglia. Activated astrocytes and microglia survive the toxic onslaught, whereas neurons and oligodendrocytes increasingly die. However, we have shown that highly selective allosteric CaSR antagonists (calcilytics), like NPS 2143 and NPS 89626, efficiently suppress all the neurotoxic effects Aβ42-os•CaSR signaling drives in cultured cortical untransformed human neurons and astrocytes. In fact, calcilytics increase Aβ42 proteolysis and discontinue the oversecretion of Aβ42-os, nitric oxide, and vascular endothelial growth factor-A from both astrocytes and neurons. Seemingly, calcilytics would also benefit the other types of glial cells and cerebrovascular cells otherwise damaged by the effects of Aβ42-os•CaSR signaling. Thus, given at amnestic minor cognitive impairment (aMCI) or initial symptomatic stages, calcilytics could prevent or terminate the propagation of LOAD neuropathology and preserve human neurons' viability and hence patients' cognitive abilities.

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Section: Interactions Between Neurons and Astrocytes In Loadmentioning

confidence: 99%

Section: Alzheimer's Disease (Ad): An Introductionmentioning

confidence: 99%

Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease

et al. 2016

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“…Stem cells may also offer a powerful new approach to model and study PD and AD. 52,53 We studied the effect of transplantation of the induced pluripotent stem cells and the human umbilical blood-derived stem cells to PD or AD animal models in our laboratory and found a significant symptomatic recovery. 54,55 In future, we would also like to combine the transplantation of stem cells and coinjection of ephrin-A1 and PDGF-BB to cure the neurodegenerative disease in PD and AD animal models.…”

mentioning

confidence: 99%

Direct interaction of receptor tyrosine kinases, EphA4 and PDGFRβ, plays an important role in the proliferation of neural stem cells

Chen¹,

Sawada²,

Sakaguchi³

et al. 2017

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Abstract:Receptor tyrosine kinases mediate the extracellular signals and transmit them into the cytoplasm by activating intracellular proteins through tyrosine phosphorylation. Both Ephs and platelet-derived growth factor (PDGF) receptors (PDGFRs) have been implicated in neurogenesis, but the functional interaction between these two pathways is poorly understood. Here, we demonstrated that EphA4 directly interacts with PDGFRβ and mutually activates each other when expressed in HEK293T cells. H9-derived neural stem cells express Ephs and PDGFRs, and their proliferation is stimulated by ephrin-A1 and PDGF-BB with further augmentation by their combined application. As both EphA4 and PDGFRβ play important roles in preventing neurodegeneration and promoting neuroprotection, their interaction and transactivation might transduce the signal through the EphA4/PDGFRβ complex and augment the proliferation of neural stem cells.

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“…These drugs are only able to target symptoms of AD and decrease the speed of progression of the disease. However, many patients do not respond to these drugs or the drugs have no profound effects on alteration of the process of AD (Han et al, 2015 ).…”

Section: Current Treatmentmentioning

confidence: 99%

“…Neurological diseases, such as frontotemporal dementia, stroke-induced vascular dementia, and Alzheimer’s disease (AD), are characterized by the impairment of memory and cognitive functions (Han et al, 2015 ). More than 80% of dementia cases are caused by AD, which is categorized as one of the most occurring neurodegenerative diseases in the world (Anand et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Biomaterials for the Treatment of Alzheimer’s Disease

Hadavi

Poot

2016

Front. Bioeng. Biotechnol.

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Alzheimer’s disease (AD) as a progressive and fatal neurodegenerative disease represents a huge unmet need for treatment. The low efficacy of current treatment methods is not only due to low drug potency but also due to the presence of various obstacles in the delivery routes. One of the main barriers is the blood–brain barrier. The increasing prevalence of AD and the low efficacy of current therapies have increased the amount of research on unraveling of disease pathways and development of treatment strategies. One of the interesting areas for the latter subject is biomaterials and their applications. This interest originates from the fact that biomaterials are very useful for the delivery of therapeutic agents, such as drugs, proteins, and/or cells, in order to treat diseases and regenerate tissues. Recently, manufacturing of nano-sized delivery systems has increased the efficacy and delivery potential of biomaterials. In this article, we review the latest developments with regard to the use of biomaterials for the treatment of AD, including nanoparticles and liposomes for delivery of therapeutic compounds and scaffolds for cell delivery strategies.

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Research progress in animal models and stem cell therapy for Alzheimer’s disease

Cited by 7 publications

References 98 publications

Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease

Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease

Direct interaction of receptor tyrosine kinases, EphA4 and PDGFRβ, plays an important role in the proliferation of neural stem cells

Biomaterials for the Treatment of Alzheimer’s Disease

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Research progress in animal models and stem cell therapy for Alzheimer&rsquo;s disease

Cited by 7 publications

References 98 publications

Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease

Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease

Direct interaction of receptor tyrosine kinases, EphA4 and PDGFR&beta;, plays an important role in the proliferation of neural stem cells

Biomaterials for the Treatment of Alzheimer’s Disease

Contact Info

Product

Resources

About

Research progress in animal models and stem cell therapy for Alzheimer’s disease

Direct interaction of receptor tyrosine kinases, EphA4 and PDGFRβ, plays an important role in the proliferation of neural stem cells