A5043045145- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- Cholesterol and Lipid Metabolism
- Functional Brain Connectivity Studies
- Dementia and Cognitive Impairment Research
- Protein Structure and Dynamics
- Lipoproteins and Cardiovascular Health
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Prion Diseases and Protein Misfolding
- Biotin and Related Studies
- 14-3-3 protein interactions
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Nuclear Receptors and Signaling
- Receptor Mechanisms and Signaling
- Advanced Neuroimaging Techniques and Applications
- Asthma and respiratory diseases
- Bioinformatics and Genomic Networks
- Click Chemistry and Applications
- Tryptophan and brain disorders
- Health and Medical Studies
- Respiratory and Cough-Related Research
- Cancer Research and Treatment
- Adipose Tissue and Metabolism
McGill University
2015-2025
Bell (Canada)
2022
Danish Medical Association
2019-2020
Municipal Institute for Medical Research
2018
Hospital Del Mar
2018
Universidade Federal de Minas Gerais
2017
Charité - Universitätsmedizin Berlin
2017
Jena University Hospital
2017
Freie Universität Berlin
2006-2015
Institute of Molecular Biology and Biophysics
2014
A key event in the pathogenesis of Alzheimer’s disease (AD) is accumulation amyloid-β (Aβ) species brain, derived from sequential cleavage amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore effect lansoprazole, other proton-pump inhibitors (PPIs), Aβ production AD cellular animal models. We found that lansoprazole enhances Aβ37, Aβ40 Aβ42 lowers Aβ38 levels cell Interestingly, acute treatment wild type transgenic...
The amyloid β (Aβ) peptide, which is abundantly found in the brains of patients suffering from Alzheimer disease, central pathogenesis this disease. Therefore, to understand processing precursor protein (APP) critical importance. Recently, we demonstrated that metalloprotease meprin cleaves APP and liberates soluble N-terminal (N-APP) fragments. In work, present evidence can also process a manner reminiscent β-secretase. We identified cleavage sites sequence wild type Swedish mutant at...
Processing of the amyloid precursor protein (APP) by γ-secretase results in generation Aβ peptides different lengths ranging from 51 to 30 residues. Accumulation and particular Aβ42 is enhanced familial Alzheimer disease (FAD) causing mutations APP believed play a pivotal role. The molecular mechanism underlying normal production, impact FAD on this process how anti-amyloidogenic modulators (GSMs) cause selective decrease Aβ40 an increase shorter peptides, however, poorly understood. By...
The angiotensin type 2 receptor (AT2R) and the MAS are receptors of protective arm renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked effects agonists vice versa. Such cross-inhibition may indicate heterodimerization these receptors. Therefore, this study investigated molecular functional interplay between AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer cross correlation spectroscopy...
Following ectodomain shedding by β-secretase, successive proteolytic cleavages within the transmembrane sequence (TMS) of amyloid precursor protein (APP) catalyzed γ-secretase result in release amyloid-β (Aβ) peptides variable length. Aβ with 42 amino acids appear to be key pathogenic species Alzheimer’s disease, as they are believed initiate neuronal degeneration. Sulindac sulfide, which is known a potent modulator (GSM), selectively reduces Aβ42 production favor shorter species, such Aβ38....
The molecular association between APP and its mammalian homologs has hardly been explored. In systematically addressing this issue, we show by live cell imaging that APLP1 mainly localizes to the surface, whereas APLP2 are mostly found in intracellular compartments. Homo- heterotypic cis interactions of family members could be detected FRET co-immunoprecipitation analysis occur a modular mode. Only formed trans interactions, supporting argument for putative specific role adhesion. Deletion...
The aggregation of the amyloid-β (Aβ) peptide plays a pivotal role in pathogenesis Alzheimer9s disease, as soluble oligomers are intimately linked to neuronal toxicity and inhibition hippocampal long-term potentiation (LTP). In C-terminal region Aβ there three consecutive GxxxG dimerization motifs, which we could previously demonstrate play critical generation Aβ. Here, show that glycine 33 (G33) central interaction motif within hydrophobic sequence is important for dynamics peptide....
Numerous studies have implicated the abnormal accumulation of intraneuronal amyloid-β (Aβ) as an important contributor to Alzheimer’s disease (AD) pathology, capable triggering neuroinflammation, tau hyperphosphorylation and cognitive deficits. However, occurrence pathological relevance intracellular Aβ remain a matter controversial debate. In this study, we used multidimensional approach including high-magnification super-resolution microscopy, cerebro-spinal fluid (CSF) mass spectrometry...
We found previously by fluorescence resonance energy transfer experiments that amyloid precursor protein (APP) homodimerizes in living cells. APP homodimerization is likely to be mediated two sites of the ectodomain and a third site within transmembrane sequence APP. have now investigated role N-terminal growth factor-like domain dimerization NMR, biochemical, cell biological approaches. Under nonreducing conditions, formed SDS-labile SDS-stable complexes. The presence SDS was sufficient...
Here, we describe a novel missense mutation in the amyloid precursor protein (APP) causing lysine-to-asparagine substitution at position 687 (APP770; herein, referred to as K16N according amyloid-β (Aβ) numbering) resulting an early onset dementia with autosomal dominant inheritance pattern. The is located exactly α-secretase cleavage site and influences both APP Aβ. First, due secretion affected higher amount of Aβ peptides being produced. Second, carrying are unique that peptide itself not...
The identification of hereditary familial Alzheimer disease (FAD) mutations in the amyloid precursor protein (APP) and presenilin-1 (PS1) corroborated causative role amyloid-beta peptides with 42 amino acid residues (Abeta42) pathogenesis AD. Although most FAD are known to increase Abeta42 levels, within APP GxxxG motif lower levels by attenuating transmembrane sequence dimerization. Here, we show that aberrant can be rescued mutations. combination APP-GxxxG mutation G33A APP-FAD yielded a...
Abstract Amyloid plaques consisting of aggregated Aβ peptide are a hallmark Alzheimer's disease. Among the different forms Aβ, one 42aa length (Aβ42) is most aggregation-prone and also neurotoxic. We find that eye-specific expression human Aβ42 in Drosophila results degeneration eye structures progresses with age. Dietary supplements zinc or copper ions exacerbate damage. Positive effects seen zinc/copper chelators, elevated MTF-1, transcription factor key role metal homeostasis...
Abstract We present a test-retest dataset of resting-state fMRI data obtained in 80 cognitively normal elderly volunteers enrolled the “Pre-symptomatic Evaluation Novel or Experimental Treatments for Alzheimer's Disease” (PREVENT-AD) Cohort. Subjects with family history disease first-degree relatives were recruited as part an on-going double blind randomized clinical trial Naproxen placebo. Two pairs scans acquired ~3 months apart, allowing assessment both intra- and inter-session...
Characteristic cerebral pathological changes of Alzheimer's disease (AD) such as glucose hypometabolism or the accumulation cleavage products amyloid precursor protein (APP), known Aβ peptides, lead to sustained endoplasmic reticulum (ER) stress and neurodegeneration. To preserve ER homeostasis, cells activate their unfolded response (UPR). The rhomboid-like-protease 4 (RHBDL4) is an enzyme that participates in UPR by targeting proteins for proteasomal degradation. We demonstrated previously...
Abstract Plasma fibronectin (pFN) is a hepatocyte‐derived circulating extracellular matrix protein that affects cell morphology, adipogenesis, and insulin signaling of adipocytes in vitro. In this study, we show pFN accrual to adipose tissue its contribution homeostasis mice. Hepatocyte‐specific conditional Fn1 knockout mice ( −/−ALB) decrease FN levels enhanced sensitivity subcutaneous (inguinal), visceral (epididymal) on normal diet. Diet‐induced obesity model the −/−ALB mouse showed...
Abstract Parkinson’s disease (PD) is marked by the death of neuromelanin-rich dopaminergic and noradrenergic cells in substantia nigra (SN) locus coeruleus (LC), respectively, resulting motor cognitive impairments. While SN dopamine dysfunction has clear neurophysiological effects, association reduced LC norepinephrine signaling with brain activity PD remains to be established. We used neuromelanin-sensitive T1-weighted MRI (NPD = 58; NHC 27) task-free magnetoencephalography 65) identify...
Measuring interactions between macromolecules is essential for elucidating their dynamics in solution and critical the design study of potential therapeutics. Fluorescence anisotropy has been a powerful widely used tool studying binding interactions. When fluorescent partner excited with polarized light while bound to its cognate ligand, emitted partially polarized. This process dependent on concentration molecules, permitting determination affinity. Here, we outline highly modular...
Abstract Alzheimer's disease is associated with pre-symptomatic changes in brain morphometry and accumulation of abnormal tau amyloid-beta pathology. Studying the development prior to symptoms onset may lead early diagnostic biomarkers a better understanding pathophysiology. pathology thought arise from combination protein spreading via neural connections, but how these processes influence atrophy progression phases remains unclear. Individuals family history (FHAD) have an elevated risk...