Multi-faced neuroprotective effects of geniposide depending on the RAGE-mediated signaling in an Alzheimer mouse model

Lv, Chen; Wang, Lei; Liu, Xiaoli; Yan, Shijun; Yan, Shirley ShiDu; Wang, Yongyan; Zhang, Wensheng

doi:10.1016/j.neuropharm.2014.09.019

Cited by 85 publications

(46 citation statements)

References 58 publications

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“…Such ligands include AGEs, Ab in AD, high mobility group box-1 protein, (HMGB1, amphoterin), S100, Mac-1 and phosphatidylserine (Bierhaus et al 2005;Opatrna et al 2014). RAGE-ligand interactions results in activation of a variety of signaling pathways including oxidative stress and activation of NF-jB and subsequent proinflammatory response (Franko et al 2014;Tancharoen et al 2014;Di et al 2015;Lv et al 2015). The conjunction of AGEs with RAGE makes further mechanisms, such as hexosamine pathway, polyol pathway, lipid metabolism disorder, activation of proteinkinase C, oxidative stress, and inflammatory reaction which all take part in the pathogenesis of diabetes, aging process, and neurodegenerative disorders (Kalousova and Zima 2014; Salahuddin et al 2014).…”

Section: Ages and Ragementioning

confidence: 99%

Role of RAGE in Alzheimer’s Disease

et al. 2015

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Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.

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Section: Ages and Ragementioning

confidence: 99%

Role of RAGE in Alzheimer’s Disease

et al. 2015

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“…Moreover, we are using immunocytochemical analysis of synapses from control and familial AD hiPSCderived neurons. These data would allow us to verify the reported differences in mEPSC amplitude and frequency (Lv et al, 2015, Neuropharmacology) and alterations in synapse structures (Almeida et al, 2005, Neurobiol Dis). In parallel, we are establishing hiPSC-derived neuron-astrocyte co-cultures with hiPSC lines from sporadic AD patients in which we intend to dissect the contribution of neurons versus astroglia to electrophysiological and structural synaptic hallmarks of AD.…”

Section: T05-059cmentioning

confidence: 75%

GLIA Edinburgh 2017: Abstracts Oral Presentations, Posters, Indexes

2017

Glia

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The chronic inflammatory demyelinating disease multiple sclerosis is characterized by multifocal demyelinating lesions, loss of oligodendrocytes (OLG) and subsequent axonal damage. Remyelination occurs in MS lesions and requires proliferation, migration and differentiation of adult oligodendroglial progenitor cells (OPCs) into mature, myelinating oligodendrocytes. It has been shown that in acute lesions OPCs accumulate at the lesion border and fail to migrate sufficiently into demyelinated lesion areas. Therefore, promotion of the migratory capacity of OPCs into demyelinated areas could be a promising target of new therapy strategies to enhance remyelination. Furthermore, differences between oligodendroglial progenitor cell populations from different CNS locations have been recently emerged; however it is unclear whether this contributes to the variable extent of remyelination observed in MS lesions localized in different CNS regions. We used primary OPCs isolated from either cerebrum or spinal cord using the panning method. In our cultures we observed a significant and reproducible difference in the migratory capacity of OPCs originating from either cerebrum (cOPC) or spinal cord (scOPC) indicating a cell intrinsic mechanism of migratory capability. To date, it is postulated that OPC migration is regulated by complex interactions of inand extrinsic factors. Under the same environmental conditions in vitro, undirected as well as directed migration towards a PDGF gradient is strongly increased in scOPC. Exposure of other factors known to modulate OPC migration (e.g. bFGF, Endothelin-1) did not exhibit remarkable differences between cOPCs or scOPC. To identify candidate genes that contribute to the migratory phenotype of scOPCs we performed genes between cOPCs and scOPCs, which are involved in cell migration or polarity. These candidate genes were further verified by q-RT-PCR in neonatal as well as adult OPCs. One of the analyzed genes is Skap2, a scr-kinase associated protein, which is a downstream target of Fyn kinase and was previously identified to play a role in migration and adhesion of other cell types i.e. macrophages. In vitro lentiviral knockdown with Skap2 shRNAs decreased migration of OPCs, but did not influence differentiation into mature oligodendrocytes. Thus, our data indicates the potential involvement of Skap2 in regulation of OPC migration. Spinal cord injury (SCI) results in neural loss and consequently motor and sensory deficit below the injury. Here we have report the regenerative effects and significant improvement of locomotor function in complete transection rat model of SCI following transplantation of oligodendrocyte progenitors cells (OPC) and motoneuron progenitors (MP) derived from hESC. Transplantation of these progenitors promote astrogliosis, thorough activation of jagged1-dependent Notch and Jak/STAT signalling supporting axonal survival. Induction of astrogliosis and neurogenesis can be achieved by inhibition of glycogen synthase kinase-3 (GSK3) well known molecule involved in se...

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“…Recent studies demonstrate that geniposide significantly blocks RAGE-dependent signaling (activation of ERK and NF-κB), with Aβ induced along with the production of TNF-α and IL-1β. Notably, based on the data from coimmunoprecipitation assay, they infer that geniposide exerts protective effects on the Aβ-induced inflammatory response through blocking Aβ binding to RAGE and suppressing the RAGE-mediated signaling pathway (Lv et al, 2015). Taking those together, RAGE may be a target for a novel AD therapy.…”

Section: Inhibition Of Chronic Inflammation In Ad By Geniposidementioning

confidence: 99%

Neuroprotective effects of geniposide on Alzheimer’s disease pathology

Liu

Hölscher³

et al. 2015

Reviews in the Neurosciences

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AbstractA growing body of evidence has linked two of the most common aged-related diseases: type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). It has led to the notion that drugs developed for the treatment of T2DM may be beneficial in modifying the pathophysiology of AD. As a receptor agonist of glucagon-like peptide-1 (GLP-1R), which is a newer drug class to treat T2DM, geniposide shows clear effects in inhibiting pathological processes underlying AD, such as promoting neurite outgrowth. In the present article, we review the possible molecular mechanisms of geniposide to protect the brain from pathologic damages underlying AD: reducing amyloid plaques, inhibiting τ phosphorylation, preventing memory impairment and loss of synapses, reducing oxidative stress and the chronic inflammatory response, and promoting neurite outgrowth via the GLP-1R signaling pathway. In summary, the Chinese herb geniposide shows great promise as a novel treatment for AD.

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Multi-faced neuroprotective effects of geniposide depending on the RAGE-mediated signaling in an Alzheimer mouse model

Cited by 85 publications

References 58 publications

Role of RAGE in Alzheimer’s Disease

Role of RAGE in Alzheimer’s Disease

GLIA Edinburgh 2017: Abstracts Oral Presentations, Posters, Indexes

Neuroprotective effects of geniposide on Alzheimer’s disease pathology

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