A5030267777- Alzheimer's disease research and treatments
- Peptidase Inhibition and Analysis
- Cancer-related Molecular Pathways
- Endoplasmic Reticulum Stress and Disease
- Cholinesterase and Neurodegenerative Diseases
- Nuclear Receptors and Signaling
- Parkinson's Disease Mechanisms and Treatments
- Epigenetics and DNA Methylation
- Neuropeptides and Animal Physiology
- Autophagy in Disease and Therapy
- Computational Drug Discovery Methods
- Medicinal Plants and Neuroprotection
- 14-3-3 protein interactions
- Cell death mechanisms and regulation
- Ubiquitin and proteasome pathways
- Neuroscience and Neuropharmacology Research
- Machine Learning in Bioinformatics
- Protease and Inhibitor Mechanisms
- Hedgehog Signaling Pathway Studies
- Genetics, Aging, and Longevity in Model Organisms
- Genetics and Neurodevelopmental Disorders
- Neurogenesis and neuroplasticity mechanisms
- Drug Transport and Resistance Mechanisms
- Axon Guidance and Neuronal Signaling
- RNA regulation and disease
Inserm
2016-2021
Université Côte d'Azur
2016-2021
Institut de Pharmacologie Moléculaire et Cellulaire
2009-2021
Centre National de la Recherche Scientifique
2006-2021
Icahn School of Medicine at Mount Sinai
2012
Fondation pour la Recherche Médicale
2009-2011
Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated β-amyloid precursor protein (βAPP swe ), P310L-Tau (Tau P301L and physiological levels of M146V-presenilin-1 (PS1 M146V ) display extracellular amyloid-β peptides (Aβ) deposits Tau tangles. More disputed is the observation that these accumulate intraneuronal Aβ has been linked to synaptic dysfunction cognitive deficits. Here, we provide immunohistological, genetic, pharmacological evidences for early, age-dependent,...
Abstract p53 is a transcription factor that implicated in the control of both apoptotic and autophagic cell death. This tumor suppressor elicits pro-autophagic anti-autophagic phenotypes depending its intracellular localization. The ability to repress autophagy has been exclusively associated cytoplasmic Here, we show transcriptional activity also contributes down-regulation. Thus, nuclear controls PINK1, key protein involved mitophagy, by repressing promoter activity, mRNA levels, ex-vivo...
Neuronal network dysfunction and cognitive decline constitute the most prominent features of Alzheimer's disease (AD), although mechanisms causing such impairments are yet to be determined. Here we report that virus-mediated delivery active spliced transcription factor X-Box binding protein 1s (XBP1s) in hippocampus rescued spine density, synaptic plasticity memory function a mouse model AD. XBP1s transcriptionally activated Kalirin-7 (Kal7), controls plasticity. In addition, found reduced...
BackgroundMitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer's disease–affected brains by yet unexplained mechanisms.MethodsWe combined cell biology, molecular pharmacological approaches to unravel a novel pathway which presenilins control phosphatase tensin homolog–induced kinase 1 (Pink-1) expression transcription. In vivo were carried out on various transgenic knockout animals as well...
Proteolytic degradation has emerged as a key pathway involved in controlling levels of the Alzheimer's disease (AD)-associated amyloid-β peptides (Aβ) brain. The ectopeptidase, neprilysin (NEP), been reported major Aβ-degrading enzyme mice and human brains. We have previously s hown that NEP expression activity are regulated by AICD, intracellular domain protein precursor (AβPP) generated γ-secretase. Thus, transcription, expression, enzymatic dramatically reduced fibroblasts devoid AβPP...
The amyloid cascade hypothesis, which proposes a prominent role for full-length β peptides in Alzheimer's disease, is currently being questioned. In addition to peptide, several N-terminally truncated fragments of peptide could well contribute disease setting and/or progression. Among them, pyroGlu3–amyloid appears be one the main components early anatomical lesions disease–affected brains. Little known about proteolytic activities that account N-terminal truncations β, but they appear as...
We established previously that α-synuclein displayed a protective anti-apoptotic phenotype in neurons, mainly by down-regulating p53-dependent caspase-3 activation (Alves da Costa, C., Ancolio, K., and Checler, F. (2000) J. Biol. Chem. 275, 24065-24069; Alves Paitel, E., Vincent, B., (2002) 277, 50980-50984). This function was abolished Parkinson disease-linked pathogenic mutations the dopaminergic toxin, 6-hydroxydopamine (6OH-DOPA) However, mechanisms which 6OH-DOPA interfered with...
Abstract We recently demonstrated that the presenilin‐dependent γ‐secretase complex regulates expression and activity of neprilysin, one main enzymes degrade amyloid β‐peptide (Aβ) which accumulates in Alzheimer's disease. Here, we examined influence endogenous nicastrin (NCT), a member complex, on neprilysin physiology. show deficiency drastically lowers expression, membrane‐bound mRNA levels, but it did not modulate two other putative Aβ‐cleaving enzymes, endothelin‐converting enzyme...
Abstract One of the main components senile plaques in Alzheimer’s disease (AD)-affected brain is Aβ peptide species harboring a pyroglutamate at position three pE3-Aβ. Several studies indicated that pE3-Aβ toxic, prone to aggregation and serves as seed aggregation. The cyclisation glutamate residue produced by glutaminyl cyclase, pharmacological genetic reductions which significantly alleviate AD-related anatomical lesions cognitive defects mice models. 3 requires prior removal N-terminal...
Abstract The aspartyl protease β-site APP cleaving enzyme, BACE1, is the rate-limiting enzyme involved in production of amyloid-β peptide, which accumulates both sporadic and familial cases Alzheimer’s disease at center gravity amyloid cascade hypothesis. In this context, unravelling molecular mechanisms controlling BACE1 expression activity physiological pathological conditions remains major importance. We previously demonstrated that Aβ controlled transcription an NFκB-dependent manner....
The presenilin-dependent gamma-secretase activity, which is responsible for the generation of amyloid beta-peptide, a high molecular weight complex composed at least four components, namely, presenilin-1 (or presenilin-2), nicastrin, Aph-1, and Pen-2. Previous data indicated that presenilins, are thought to harbor catalytic core complex, also control p53-dependent cell death. Whether other components could modulate death process in mammalian neurons remained be established. Here, we examined...
The senile plaques found in the brains of patients with Alzheimer's disease are mainly due to accumulation amyloid β-peptides (Aβ) that liberated by γ-secretase, a high molecular weight complex including presenilins, PEN-2, APH-1 and nicastrin. depletion each these proteins disrupts assembly into functional protease. Here, we describe another level regulation this multimeric both presenilins drastically reduces Pen2 mRNA levels its promoter transactivation. Furthermore, overexpression...
Abstract Nicastrin (NCT) is a component of the presenilin (PS)‐dependent γ‐secretase complexes that liberate amyloid β‐peptides from β‐Amyloid Precursor Protein. Several lines evidence indicate members these could also contribute to control cell death. Here we show over‐expression NCT increases viability human embryonic kidney (HEK293) cells and decreases staurosporine (STS)‐ thapsigargin (TPS)‐induced caspase‐3 activation in various neuronal origins by Akt‐dependent pathway. lowers p53...
PS (presenilin)-dependent gamma-secretase occurs as a high-molecular-mass complex composed of either PS1 or PS2 associated with Nct (nicastrin), PEN2 (presenilin enhancer 2 homologue) and APH1 (anterior pharynx defective 1 homologue). Numerous reports have documented the very complicated physical functional cross-talk between these proteins that ultimately governs biological activity gamma-secretase, but few studies examined fate components complex. We show that, in both HEK-293 cells TSM1...
The presenilin-dependent γ-secretase complex is mainly composed of four distinct proteins, namely presenilin 1 or 2, nicastrin, anterior pharynx defective-1 (Aph-1) and enhancer (Pen-2). mechanisms by which the assembled, how its stochiometry controlled catalytic activity regulated are poorly understood. Recent studies indicated that Aph-1 Pen-2 undergo proteolysis proteasome. We have examined susceptibility endogenous overexpressed Aph-1a to purified proteasome as well recombinant caspases....
Background Triple-transgenic mice (3xTgAD) overexpressing Swedish-mutated b-amyloid-precursor-protein (APPswe), P310L-Tau (TauP301L) and physiological levels of M146Vpresenilin-1 (PS1M146V) display extracellular amyloid-beta peptides (Abeta) deposits Tau tangles at late ages. These also show an early, age-dependent hippocampus specific accumulation intra-neuronal APPrelated materiel, which was firstly reported to correspond Abeta. However, more recent work has disputed the presence Abeta...