The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Falk Fahrenholz - One of the best experts on this subject based on the ideXlab platform.

  • Regulation of Alpha-Secretase ADAM10 expression and activity
    Experimental Brain Research, 2012
    Co-Authors: Kristina Endres, Falk Fahrenholz
    Abstract:

    The amyloid precursor protein (APP) has a pivotal role in pathogenesis of Alzheimer’s disease (AD) via its beta- and gamma-Secretase-derived cleavage products—the A-beta peptides. An alternative processing pathway provided by the Alpha-Secretase prevents formation of those toxic peptides and gives rise to the neurotrophic and neuroprotective cleavage product APPs-Alpha. The molecular identity of the Alpha-Secretase has been confirmed recently, and there is consistency about ADAM10 being the most relevant and physiological enzyme of this class. It is not clear to what extent a deficiency in the catalytic activity of ADAM10 contributes to AD pathology and whether a decline occurs in aging humans. Nevertheless, ADAM10 has been suggested as a valuable target for prevention and/or for treatment of Alzheimer’s disease. This review focuses on our knowledge about regulation of ADAM10 on different levels of cell physiology, such as transcription and translation, as well as protein–protein interactions and how this especially in the case of transcriptional regulation by retinoic acids might lead to the development of new therapeutic approaches.

  • acitretin an enhancer of Alpha Secretase expression crosses the blood brain barrier and is not eliminated by p glycoprotein
    Neurodegenerative Diseases, 2012
    Co-Authors: David Holthoewer, Kristina Endres, Florian Schuck, Ulrich Schmitt, Christoph Hiemke, Falk Fahrenholz
    Abstract:

    Background: ADAM10 (a disintegrin and metalloproteinase 10) has been demonstrated to act as the main physiological α-Secretase. Enzymatic activity of the α-Secretase on the one hand prevents the formation of toxic Aβ peptides and on the other hand promotes the secretion of a neurotrophic and neuroprotective amyloid precursor protein fragment (APPs-α) by cleaving the amyloid precursor protein within its Aβ sequence. Enhancement of ADAM10’s gene expression may therefore present a valuable therapeutic approach for the treatment of Alzheimer’s disease (AD), where Aβ peptides are severely involved in the pathogenesis. Objective: In cell culture and in a transgenic mouse model of AD, retinoids led to increased ADAM10 expression and activity. We therefore endeavor to develop a clinical application of synthetic retinoids such as acitretin in AD. Methods: The effect of synthetic retinoids on ADAM10 gene expression was analyzed by reporter gene assays in human neuroblastoma cell line SH-SY5Y. Penetrance of acitretin into the murine brain was analyzed by high-performance liquid chromatography. P-glycoprotein (P-gp) double-knockout mice with a deficiency in both isoforms, mdr1a and 1b, were used to analyze a possible role of P-gp-dependent efflux on acitretin distribution. Results: Acitretin and tamibarotene are both potent activators of ADAM10 promoter activity. Acitretin crosses the murine blood-brain barrier and its level in the mouse brain is not reduced by P-gp. Conclusion: Synthetic retinoids and especially acitretin seem to be ideal candidates to establish an ADAM10-based AD treatment, and therefore have already entered first clinical trials.

  • up regulation of the Alpha Secretase adam10 by retinoic acid receptors and acitretin
    The FASEB Journal, 2009
    Co-Authors: Frank Tippmann, Kristina Endres, Jana Hundt, Anja Schneider, Falk Fahrenholz
    Abstract:

    Late-onset Alzheimer's disease is often connected with nutritional misbalance, such as enhanced cholesterol intake, deficiency in polyunsaturated fatty acids, or hypovitaminosis. The Alpha-Secretase ADAM10 has been found to be regulated by retinoic acid, the bioreactive metabolite of vitamin A. Here we show that retinoids induce gene expression of ADAM10 and Alpha-Secretase activity by nonpermissive retinoid acid receptor/retinoid X receptor (RAR/RXR) heterodimers, whereby Alpha- and beta-isotypes of RAR play a major role. However, ligands of other RXR binding partners, such as the vitamin D receptor, do not stimulate Alpha-Secretase activity. On the basis of these findings, we examined the effect of synthetic retinoids and found a strong enhancement of nonamyloidogenic processing of the amyloid precursor protein by the vitamin A analog acitretin: it stimulated ADAM10 promoter activity with an EC50 of 1.5 mu M and led to an increase of mature ADAM10 protein that resulted in a two- to three-fold increase of the ratio between Alpha- and beta-Secretase activity in neuroblastoma cells. The Alpha-Secretase stimulation by acitretin was completely inhibited by the ADAM10-specific inhibitor GI254023X. Intracerebral injection of acitretin in APP/PS1-21 transgenic mice led to a reduction of A beta(40) and A beta(42). The results of this study may have clinical relevance because acitretin has been approved for the treatment of psoriasis since 1997 and found generally safe for long-term use in humans.-Tippmann, F., Hundt, J., Schneider, A., Endres, K., Fahrenholz, F. Up-regulation of the Alpha-Secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 23, 1643-1654 (2009)

  • Up-regulation of the α-Secretase ADAM10 by retinoic acid receptors and acitretin
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2009
    Co-Authors: Frank Tippmann, Kristina Endres, Jana Hundt, Anja Schneider, Falk Fahrenholz
    Abstract:

    Late-onset Alzheimer's disease is often connected with nutritional misbalance, such as enhanced cholesterol intake, deficiency in polyunsaturated fatty acids, or hypovitaminosis. The Alpha-Secretase ADAM10 has been found to be regulated by retinoic acid, the bioreactive metabolite of vitamin A. Here we show that retinoids induce gene expression of ADAM10 and Alpha-Secretase activity by nonpermissive retinoid acid receptor/retinoid X receptor (RAR/RXR) heterodimers, whereby Alpha- and beta-isotypes of RAR play a major role. However, ligands of other RXR binding partners, such as the vitamin D receptor, do not stimulate Alpha-Secretase activity. On the basis of these findings, we examined the effect of synthetic retinoids and found a strong enhancement of nonamyloidogenic processing of the amyloid precursor protein by the vitamin A analog acitretin: it stimulated ADAM10 promoter activity with an EC50 of 1.5 mu M and led to an increase of mature ADAM10 protein that resulted in a two- to three-fold increase of the ratio between Alpha- and beta-Secretase activity in neuroblastoma cells. The Alpha-Secretase stimulation by acitretin was completely inhibited by the ADAM10-specific inhibitor GI254023X. Intracerebral injection of acitretin in APP/PS1-21 transgenic mice led to a reduction of A beta(40) and A beta(42). The results of this study may have clinical relevance because acitretin has been approved for the treatment of psoriasis since 1997 and found generally safe for long-term use in humans.-Tippmann, F., Hundt, J., Schneider, A., Endres, K., Fahrenholz, F. Up-regulation of the Alpha-Secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 23, 1643-1654 (2009)

  • adam 10 over expression increases cortical synaptogenesis
    Neurobiology of Aging, 2008
    Co-Authors: Karen F S Bell, Falk Fahrenholz, Luyu Zheng, Claudio A Cuello
    Abstract:

    Cortical cholinergic, glutamatergic and GABAergic terminals become upregulated during early stages of the transgenic amyloid pathology. Abundant evidence suggests that sAPP Alpha, the product of the non-amyloidogenic Alpha-Secretase pathway, is neurotrophic both in vitro and when exogenously applied in vivo. The disintegrin metalloprotease ADAM-10 has been shown to have Alpha-Secretase activity in vivo. To determine whether sAPP Alpha has an endogenous biological influence on cortical presynaptic boutons in vivo, we quantified cortical cholinergic, glutamatergic and GABAergic presynaptic bouton densities in either ADAM-10 moderate expressing (ADAM-10 mo) transgenic mice, which moderately overexpress ADAM-10, or age-matched non-transgenic controls. Both early and late ontogenic time points were investigated. ADAM-10 mo transgenic mice display significantly elevated cortical cholinergic, glutamatergic and GABAergic presynaptic bouton densities at the early time point (8 months). Only the cholinergic presynaptic bouton density remains significantly elevated in late-staged ADAM-10 mo transgenic animals (18 months). To confirm that the observed elevations were due to increased levels of endogenous murine sAPP Alpha, exogenous human sAPP Alpha was infused into the cortex of non-transgenic control animals for 1 week. Exogenous infusion of sAPP Alpha led to significant elevations in the cholinergic, glutamatergic and GABAergic cortical presynaptic bouton populations. These results are the first to demonstrate an in vivo influence of ADAM-10 on neurotransmitter-specific cortical synaptic plasticity and further confirm the neurotrophic influence of sAPP Alpha on cortical synaptogenesis.

Kristina Endres - One of the best experts on this subject based on the ideXlab platform.

  • implications of Alpha and beta Secretase expression and function in alzheimer s disease
    2020
    Co-Authors: Sven Reinhardt, Kristina Endres
    Abstract:

    Abstract There has been intense debate in the field about the extent to which processing of the amyloid precursor protein contributes to pathogenesis of Alzheimer's disease. Early publications succeeding in the identification of the main component of senile plaques—the amyloid-beta (A-beta) peptide—strictly argued for a constitutive contribution of A-beta to disease initiation and progression. This led to development of the amyloid hypothesis, which in recent years was attacked for the lack of success of clinical studies based on the respective assumption. There is evidence that the hypothesis must be revisited, but accumulation of A-beta along with aging might still be the best explanation for disease development. Therefore, it is important to understand mechanisms that balance synthesis, transport, and degradation of A-beta. The main enzyme laying groundwork for A-beta production is the beta-Secretase BACE-1. Its enzymatic opponent is represented by the Alpha-Secretase ADAM10 in neurons. ADAM10 prevents formation of A-beta by cleaving within the peptide's stretch. In this chapter we focus on knowledge about balance of the two enzymes, Alpha- and beta-Secretase, in aging and disease.

  • The Synthetic Retinoid Acitretin Increases IL-6 in the Central Nervous System of Alzheimer Disease Model Mice and Human Patients
    Frontiers in aging neuroscience, 2019
    Co-Authors: Malena Dos Santos Guilherme, Nicolai M Stoye, Stefan Rose-john, Christoph Garbers, Andreas Fellgiebel, Kristina Endres
    Abstract:

    These days the important role of retinoids in adult brain functionality and homeostasis is well accepted and has been proven by genomic as well as non-genomic mechanisms. In the healthy brain, numerous biological processes e.g. cell proliferation, neurogenesis, dendritic spine formation as well as modulation of the immune system have been attributed to retinoid signaling. This, together with the finding that retinoid metabolism is impaired in Alzheimer’s disease, led to preclinical and early clinical testing of natural and synthetic retinoids as innovative pharmaceuticals with multifactorial properties. Acitretin, an aromatic retinoid, was found to exert anti-amyloidogenic effect in mouse models for Alzheimer’s disease as well as in human patients by stimulating the Alpha-Secretase ADAM10. The lipophilic drug was already demonstrated to easily pass the blood brain barrier after i.p. administration and increased nest building capability in the 5xFAD mouse model. Additionally, we analyzed the immune-modulatory capacity of acitretin via a multiplex array in the 5xFAD mouse model and evaluated some of our findings in human CSF derived from a pilot study using acitretin. Although several serum analytes did not display changes, IL-6 was found to be significantly increased in both - mouse and human neural material. This demonstrates that acitretin exerts an immune stimulatory effect – besides the Alpha-Secretase induction – which could impact the alleviation of learning and memory disabilities observed in the mouse model.

  • Identification of disulfiram as a Secretase-modulating compound with beneficial effects on Alzheimer’s disease hallmarks
    Nature Publishing Group, 2018
    Co-Authors: Sven Reinhardt, Ulrich Schmitt, Nicolai Stoye, Mathias Luderer, Falk Kiefer, Klaus Lieb, Kristina Endres
    Abstract:

    Abstract ADAM10 is a metalloproteinase acting on the amyloid precursor protein (APP) as an Alpha-Secretase in neurons. Its enzymatic activity results in secretion of a neuroprotective APP cleavage product (sAPP-Alpha) and prevents formation of the amyloidogenic A-beta peptides, major hallmarks of Alzheimer’s disease (AD). Elevated ADAM10 levels appeared to contribute to attenuation of A-beta-plaque formation and learning and memory deficits in AD mouse models. Therefore, it has been assumed that ADAM10 might represent a valuable target in AD therapy. Here we screened a FDA-approved drug library and identified disulfiram as a novel ADAM10 gene expression enhancer. Disulfiram increased ADAM10 production as well as sAPP-Alpha in SH-SY5Y human neuronal cells and additionally prevented A-beta aggregation in an in vitro assay in a dose-dependent fashion. In addition, acute disulfiram treatment of Alzheimer model mice induced ADAM10 expression in peripheral blood cells, reduced plaque-burden in the dentate gyrus and ameliorated behavioral deficits. Alcohol-dependent patients are subjected to disulfiram-treatment to discourage alcohol-consumption. In such patients, enhancement of ADAM10 by disulfiram-treatment was demonstrated in peripheral blood cells. Our data suggest that disulfiram could be repurposed as an ADAM10 enhancer and AD therapeutic. However, efficacy and safety has to be analyzed in Alzheimer patients in the future

  • Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms.
    Frontiers in molecular neuroscience, 2017
    Co-Authors: Kristina Endres, Thomas Deller
    Abstract:

    ADAM10 (A Disintegrin and Metalloproteinase 10) has been identified as the major physiological Alpha-Secretase in neurons, responsible for cleaving APP in a non-amyloidogenic manner. This cleavage results in the production of a neuroprotective APP-derived fragment, APPs-Alpha, and an attenuated production of neurotoxic A-beta peptides. An increase in ADAM10 activity shifts the balance of APP processing towards APPs-Alpha and protects the brain from amyloid deposition and disease. Thus, increasing ADAM10 activity has been proposed an attractive target for the treatment of neurodegenerative diseases and it appears to be timely to investigate the physiological mechanisms regulating ADAM10 expression. Therefore in this article, we will (1) review reports on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or protein interactions, (2) describe conditions, which change ADAM10 expression in vitro and in vivo, (3) report how neuronal ADAM10 expression may be regulated in humans, and (4) discuss how this knowledge on the physiological and pathophysiological regulation of ADAM10 may help to preserve or restore brain function.

  • Extract of Caragana sinica as a potential therapeutic option for increasing Alpha-Secretase gene expression.
    Phytomedicine : international journal of phytotherapy and phytopharmacology, 2015
    Co-Authors: Florian Schuck, Ulrich Schmitt, Sven Reinhardt, Christian Freese, Ik-soo Lee, Eckhard Thines, Thomas Efferth, Kristina Endres
    Abstract:

    Abstract Background Alzheimer's disease represents one of the main neurological disorders in the aging population. Treatment options so far are only of symptomatic nature and efforts in developing disease modifying drugs by targeting amyloid beta peptide-generating enzymes remain fruitless in the majority of human studies. During the last years, an alternative approach emerged to target the physiological Alpha-Secretase ADAM10, which is not only able to prevent formation of toxic amyloid beta peptides but also provides a neuroprotective fragment of the amyloid precursor protein – sAPPAlpha. Purpose To identify novel Alpha-Secretase enhancers from a library of 313 extracts of medicinal plants indigenous to Korea, a screening approach was used and hits were further evaluated for their therapeutic value. Methods The extract library was screened for selective enhancers of ADAM10 gene expression using a luciferase-based promoter reporter gene assay in the human neuroblastoma cell line SH-SY5Y. Candidate extracts were then tested in wild type mice for acute behavioral effects using an open field paradigm. Brain and liver tissue from treated mice was biochemically analyzed for ADAM10 gene expression in vivo . An in vitro blood–brain barrier model and an in vitro ATPase assay were used to unravel transport properties of bioactive compounds from extract candidates. Finally, fractionation of the most promising extract was performed to identify biologically active components. Results The extract of Caragana sinica (Buc'hoz) Rehder was identified as the best candidate from our screening approach. We were able to demonstrate that the extract is acutely applicable in mice without obvious side effects and induces ADAM10 gene expression in peripheral tissue. A hindered passage across the blood–brain barrier was detected explaining lack of cerebral induction of ADAM10 gene expression in treated mice. By fractionating C. sinica extract we identified Alpha-viniferin as one of the biologically active components. Conclusion The extract of C. sinica and Alpha-viniferin as one of its bioactive constituents might serve as novel therapeutic options for treating Alzheimer's disease by increasing ADAM10 gene expression. The identification of Alpha-viniferin represents a promising starting point to achieve blood–brain barrier penetrance in the future.

Mark P Mattson - One of the best experts on this subject based on the ideXlab platform.

  • neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein app in appsw mice resulting in tau phosphorylation and loss of hippocampal neurons support for the amyloid hypothesis
    The Journal of Neuroscience, 2004
    Co-Authors: Thor D Stein, Nicholas J Anders, Charles Decarli, Sic L Chan, Mark P Mattson, Jeffrey A Johnson
    Abstract:

    Alzheimer's disease (AD) may be caused by the abnormal processing of the amyloid precursor protein (APP) and the accumulation of beta-amyloid (Abeta). The amyloid precursor protein can be proteolytically cleaved into multiple fragments, many of which have distinct biological actions. Although a high level of Abeta can be toxic, the Alpha-Secretase cleaved APP (sAPPAlpha) is neuroprotective. However, the mechanism of sAPPAlpha protection is unknown. Here, we show that sAPPAlpha increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from Abeta-induced tau phosphorylation and neuronal death. Antibody interference and small interfering RNA knock-down demonstrate that the sAPPAlpha-driven expression of transthyretin and insulin-like growth factor 2 is necessary for protection against Abeta-induced neuronal death. Mice overexpressing mutant APP possess high levels of sAPPAlpha and transthyretin and do not develop the tau phosphorylation or neuronal loss characteristic of human AD. Chronic infusion of an antibody against transthyretin into the hippocampus of mice overexpressing APP with the Swedish mutation (APP(Sw)) leads to increased Abeta, tau phosphorylation, and neuronal loss and apoptosis within the CA1 neuronal field. Therefore, the elevated expression of transthyretin is mediated by sAPPAlpha and protects APP(Sw) mice from developing many of the neuropathologies observed in AD.

  • increased activity regulating and neuroprotective efficacy of α Secretase derived secreted amyloid precursor protein conferred by a c terminal heparin binding domain
    Journal of Neurochemistry, 2002
    Co-Authors: Katsutoshi Furukawa, Bryce L Sopher, Russell E Rydel, James G Begley, Dao G Pham, George M Martin, Michael A Fox, Mark P Mattson
    Abstract:

    Proteolytic cleavage of beta-amyloid precursor protein (beta APP) by Alpha-Secretase results in release of one secreted form (sAPP) of APP (sAPP Alpha), whereas cleavage by beta-Secretase releases a C-terminally truncated sAPP (sAPP beta) plus amyloid beta-peptide (A beta). beta APP mutations linked to some inherited forms of Alzheimer's disease may alter its processing such that levels of sAPP Alpha are reduced and levels of sAPP beta increased. sAPP Alpha s may play important roles in neuronal plasticity and survival, whereas A beta can be neurotoxic. sAPP Alpha was approximately 100-fold more potent than sAPP beta in protecting hippocampal neurons against excitotoxicity, A beta toxicity, and glucose deprivation. Whole-cell patch clamp and calcium imaging analyses showed that sAPP beta was less effective than sAPP Alpha in suppressing synaptic activity, activating K+ channels, and attenuating calcium responses to glutamate. Using various truncated sAPP Alpha and sAPP beta APP695 products generated by eukaryotic and prokaryotic expression systems, and synthetic sAPP peptides, the activity of sAPP Alpha was localized to amino acids 591-612 at the C-terminus. Heparinases greatly reduced the actions of sAPP Alpha s, indicating a role for a heparin-binding domain at the C-terminus of sAPP Alpha in receptor activation. These findings indicate that alternative processing of beta APP has profound effects on the bioactivity of the resultant sAPP products and suggest that reduced levels of sAPP Alpha could contribute to neuronal degeneration in Alzheimer's disease.

  • phosphatidylinositol 3 kinase akt kinase and p42 p44 mitogen activated protein kinases mediate neurotrophic and excitoprotective actions of a secreted form of amyloid precursor protein
    Experimental Neurology, 2002
    Co-Authors: Guanjun Cheng, Mark P Mattson, Daohong Zhou
    Abstract:

    The Alpha-Secretase-derived form of the amyloid precursor protein (sAPPAlpha), which is released from neurons in an activity-dependent manner, has been shown to promote long-term survival of hippocampal and cortical neurons in culture and can protect those neurons against excitotoxic and ischemic injury in culture and in vivo. The signal transduction pathway(s) activated by sAPPAlpha has not been established. We now report that sAPPAlpha activates the phosphatidylinositol-3-kinase (PI(3)K)-Akt kinase signaling pathway in cultured hippocampal neurons. sAPPAlpha also stimulates phosphorylation of p42 (ERK1) and p44 (ERK2) mitogen-activated protein (MAP) kinases by a PI(3)K-independent pathway. Treatment of neurons with sAPPAlpha protects them against death induced by trophic factor deprivation and exposure to glutamate, and these survival-promoting effects of sAPPAlpha are abolished or attenuated when either PI(3)K or p42/p44 MAP kinases are selectively blocked. Exposure of neurons to sAPPAlpha resulted in a decrease in the level of IkappaBbeta and an increase in NF-kappaB DNA binding activity, both of which were blocked by wortmannin, suggesting that the transcription factor NF-kappaB may be a downstream target of the PI(3)K-Akt pathway that may play a role in the cell survival-promoting action of sAPPAlpha. These findings suggest that the PI(3)K-Akt pathway and p42/p44 MAP kinases mediate responses of neurons to sAPPAlpha in physiological and pathological settings, with implications for synaptic plasticity and the pathogenesis of Alzheimer's disease.

Jiajian Tan - One of the best experts on this subject based on the ideXlab platform.

  • Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice
    JOURNAL OF NEUROSCIENCE, 2005
    Co-Authors: Jiajian Tan
    Abstract:

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of beta-amyloid (Abeta) peptides as senile plaques in the brain. Recent studies suggest that green tea flavonoids may be used for the prevention and treatment of a variety of neurodegenerative diseases. Here, we report that (-)-epigallocatechin-3-gallate (EGCG), the main polyphenolic constituent of green tea, reduces Abeta generation in both murine neuron-like cells (N2a) transfected with the human "Swedish" mutant amyloid precursor protein (APP) and in primary neurons derived from Swedish mutant APP-overexpressing mice (Tg APPsw line 2576). In concert with these observations, we find that EGCG markedly promotes cleavage of the Alpha-C-terminal fragment of APP and elevates the N-terminal APP cleavage product, soluble APP-Alpha. These cleavage events are associated with elevated Alpha-Secretase activity and enhanced hydrolysis of tumor necrosis factor Alpha-converting enzyme, a primary candidate Alpha-Secretase. As a validation of these findings in vivo, we treated Tg APPsw transgenic mice overproducing Abeta with EGCG and found decreased Abeta levels and plaques associated with promotion of the nonamyloidogenic Alpha-Secretase proteolytic pathway. These data raise the possibility that EGCG dietary supplementation may provide effective prophylaxis for AD.

Yves Lecarpentier - One of the best experts on this subject based on the ideXlab platform.

  • alzheimer disease crosstalk between the canonical wnt beta catenin pathway and ppars Alpha and gamma
    Frontiers in Neuroscience, 2016
    Co-Authors: Alexandre Vallee, Yves Lecarpentier
    Abstract:

    The molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) are still not fully understood. In AD, Wnt/beta-catenin signaling has been shown to be downregulated while the peroxisome proliferator-activated receptor (PPAR) gamma (mARN and protein) is upregulated. Certain neurodegenerative diseases share the same Wnt/beta-catenin/PPAR gamma profile, such as bipolar disorder and schizophrenia. Conversely, other NDs share an opposite profile, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis and Friedreich's ataxia. AD is characterized by the deposition of extracellular Abeta plaques and the formation of intracellular neurofibrillary tangles in the central nervous system . Activation of Wnt signaling or inhibition of both glycogen synthase kinase-3beta and Dickkopf 1, two key negative regulators of the canonical Wnt pathway, are able to protect against Abeta neurotoxicity and to ameliorate cognitive performance in AD patients. Although PPAR gamma is upregulated in AD patients, and despite the fact that it has been shown that the PPAR gamma and Wnt/beta catenin pathway systems work in an opposite manner, PPAR gamma agonists diminish learning and memory deficits, decrease Abeta activation of microglia, and prevent hippocampal and cortical neurons from dying. These beneficial effects observed in AD transgenic mice and patients might be partially due to the anti-inflammatory properties of PPAR gamma agonists. Moreover, activation of PPAR Alpha upregulates transcription of the Alpha-Secretase gene and represents a new therapeutic treatment for AD. This review focuses largely on the behavior of two opposing pathways in AD, namely Wnt/beta-catenin signaling and PPAR gamma. It is hoped that this approach may help to develop novel AD therapeutic strategies integrating PPAR Alpha signaling.

  • Alzheimer disease: crosstalk between the canonical Wnt/beta-catenin pathway and PPARs Alpha and gamma
    Frontiers Media S.A., 2016
    Co-Authors: Alexandre Vallee, Yves Lecarpentier
    Abstract:

    The molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) are still not fully understood. In AD, Wnt/beta-catenin signaling has been shown to be downregulated while the peroxisome proliferator-activated receptor (PPAR) gamma (mARN and protein) is upregulated. Certain neurodegenerative diseases share the same Wnt/beta-catenin/PPAR gamma profile, such as bipolar disorder and schizophrenia. Conversely, other NDs share an opposite profile, such as amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis and Friedreich's ataxia. AD is characterized by the deposition of extracellular Abeta plaques and the formation of intracellular neurofibrillary tangles in the central nervous system . Activation of Wnt signaling or inhibition of both glycogen synthase kinase-3beta and Dickkopf 1, two key negative regulators of the canonical Wnt pathway, are able to protect against Abeta neurotoxicity and to ameliorate cognitive performance in AD patients. Although PPAR gamma is upregulated in AD patients, and despite the fact that it has been shown that the PPAR gamma and Wnt/beta catenin pathway systems work in an opposite manner, PPAR gamma agonists diminish learning and memory deficits, decrease Abeta activation of microglia, and prevent hippocampal and cortical neurons from dying. These beneficial effects observed in AD transgenic mice and patients might be partially due to the anti-inflammatory properties of PPAR gamma agonists. Moreover, activation of PPAR Alpha upregulates transcription of the Alpha-Secretase gene and represents a new therapeutic treatment for AD. This review focuses largely on the behavior of two opposing pathways in AD, namely Wnt/beta-catenin signaling and PPAR gamma. It is hoped that this approach may help to develop novel AD therapeutic strategies integrating PPAR Alpha signaling