A5086409965- Alzheimer's disease research and treatments
- Neuropeptides and Animal Physiology
- Peptidase Inhibition and Analysis
- Cholinesterase and Neurodegenerative Diseases
- Prion Diseases and Protein Misfolding
- Nuclear Receptors and Signaling
- Parkinson's Disease Mechanisms and Treatments
- Cellular transport and secretion
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Autophagy in Disease and Therapy
- Neuroscience and Neuropharmacology Research
- Protein Hydrolysis and Bioactive Peptides
- Biotin and Related Studies
- Receptor Mechanisms and Signaling
- Protease and Inhibitor Mechanisms
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Amino Acid Enzymes and Metabolism
- Trace Elements in Health
- Cancer-related Molecular Pathways
- Mitochondrial Function and Pathology
- Neurological diseases and metabolism
- 14-3-3 protein interactions
- Biochemical and Structural Characterization
Institut de Pharmacologie Moléculaire et Cellulaire
2016-2025
Centre National de la Recherche Scientifique
2016-2025
Inserm
2016-2025
Institut de Biologie Moléculaire et Cellulaire
2025
Université Côte d'Azur
2014-2024
Canadian Nautical Research Society
2024
Fondation pour la Recherche Médicale
2006-2023
Observatoire de la Côte d’Azur
2006-2023
University of Toronto
2023
University Health Network
2023
Transgenic mice overexpressing different forms of amyloid precursor protein (APP), i.e. wild type or clinical mutants, displayed an essentially comparable early phenotype in terms behavior, differential glutamatergic responses, deficits maintenance long term potentiation, and premature death. The cognitive impairment, demonstrated F1 hybrids the APP transgenic lines, was significantly from nontransgenic littermates as 3 months age. Biochemical analysis secreted membrane-bound APP, C-terminal...
Mutations in the homologous presenilin 1 (PS1) and 2 (PS2) genes cause most common aggressive form of familial Alzheimer’s disease. Although PS1 function dysfunction have been extensively studied, little is known about PS2 vivo . To delineate relationships activities whether mutations involve gain or loss function, we generated homozygous deficient (−/−) PS1/PS2 double mice. In contrast to −/− mice, mice are viable fertile develop only mild pulmonary fibrosis hemorrhage with age. Absence...
In Alzheimer disease (AD), the perturbation of endoplasmic reticulum (ER) calcium (Ca²⁺) homeostasis has been linked to presenilins, catalytic core in γ-secretase complexes cleaving amyloid precursor protein (APP), thereby generating amyloid-β (Aβ) peptides. Here we investigate whether APP contributes ER Ca²⁺ and could turn influence Aβ production. We show that overexpression wild-type human (APP(695)), or harboring Swedish double mutation (APP(swe)) triggers increased ryanodine receptor...
Abstract Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger Alzheimer’s disease (AD) pathology. Altered mitochondrial homeostasis is considered early event in AD development. However, specific contribution APP-CTFs structure, function, and mitophagy defects remains be established. Here, we demonstrate neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or...
Abstract Endosomal-autophagic-lysosomal (EAL) dysfunction is an early and prominent neuropathological feature of Alzheimers’s disease, yet the exact molecular mechanisms contributing to this pathology remain undefined. By combined biochemical, immunohistochemical ultrastructural approaches, we demonstrate a link between EAL intraneuronal accumulation β-secretase-derived βAPP fragment (C99) in two vivo models, 3xTgAD mice adeno-associated viral-mediated C99-infected mice. We present...
The excessive generation and accumulation of 40- 42-aa beta-amyloid peptides (Abeta40/Abeta42) in selectively vulnerable brain regions is a major neuropathological feature Alzheimer's disease. Abeta, derived by proteolytic cleavage from the precursor protein (betaAPP), normally secreted. However, recent evidence suggests that significant levels Abeta also may remain inside cells. Here, we have investigated subcellular compartments within which distinct amyloid species are generated they...
Processing of the β-amyloid precursor protein (βAPP) by β- and γ-secretases generates amyloidogenic peptide Aβ, a major factor in etiology Alzheimer's disease. Following recent identification β-secretase β-amyloid-converting enzyme (BACE), we herein investigate its zymogen processing, molecular properties, cellular trafficking. Our data show that among proprotein convertase family members, furin is converting pro-BACE into BACE within trans-Golgi network HK293 cells. While demonstrate...
We showed previously that PrPc undergoes constitutive and phorbol ester-regulated cleavage inside the 106–126 toxic domain of protein, leading to production a fragment referred as N1. Here we show by pharmacological approach thato-phenanthroline, general zinc-metalloprotease inhibitors, well BB3103 TAPI, inhibitors metalloenzymes ADAM10 (Adisintegrinand metalloprotease); TACE,tumor necrosis factorα-converting enzyme; ADAM17), respectively, drastically reduce N1 formation. set up stable human...
The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis vitro and vivo. Here, we show directly activated the p53 promoter, resulting p53-dependent apoptosis, Abeta40 had similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of mRNA elevation guinea-pig primary neurons. Also, expression was elevated brain sporadic AD transgenic...
Different duplications of the APP locus have been identified in five families with autosomal dominant early onset Alzheimer's disease (ADEOAD) and Abeta-related cerebral amyloid angiopathy (CAA). This study describes phenotype this new entity. Clinical, neuropsychological, imagery neuropathological data were reviewed. The was not dependent on size duplication there no clinical feature Down's syndrome. Dementia observed all cases; intracerebral haemorrhage (ICH) reported 6 (26%) seizures...
Recent works suggest that alpha-synuclein could play a central role in Parkinson's disease (PD). Thus, two mutations were reported to be associated with rare autosomal dominant forms of the disease. We examined whether modulate caspase-mediated response and vulnerability murine neurons various apoptotic stimuli. established TSM1 neuronal cell lines overexpressing wild-type (wt) or PD-related Ala-53 --> Thr mutant alpha-synuclein. Under basal conditions,...
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: Neurotensin was inactivated by membrane‐bound and soluble degrading activities present in purified preparations of rat brain synaptic membranes. Degradation products were identified HPLC amino acid analysis. The major points cleavage neurotensin the Arg 8 ‐Arg 9 , Pro l0 ‐Tyr 11 Tyr ‐Ile 12 peptide bonds with activity 10 activity. Several lines evidence indicated that bond resulted mainly from conversion 1–10 to 1–8 a dipeptidyl carboxypeptidase. In particular, captopril inhibited...