A5024874982- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Neuroscience and Neuropharmacology Research
- Supramolecular Self-Assembly in Materials
- Nuclear Receptors and Signaling
- Prion Diseases and Protein Misfolding
- Natural Antidiabetic Agents Studies
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Enzyme Structure and Function
- Lipid Membrane Structure and Behavior
- Phytase and its Applications
- RNA regulation and disease
- Cellular transport and secretion
- Enzyme Production and Characterization
VIB-KU Leuven Center for Brain & Disease Research
2014-2024
VIB-KU Leuven Center for Cancer Biology
2012-2015
KU Leuven
2012-2015
Presenilin (PSEN) pathogenic mutations cause familial Alzheimer’s disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other neurodegeneration remains unclear. In this study, we assessed γ-secretase activity brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different PSEN1, 11 sporadic AD (SAD) patients. control had similar overall levels, therefore, loss of (endopeptidase) function cannot be...
γ-Secretase complexes are involved in the generation of amyloid-β (Aβ) brain. Therefore, γ-secretase has been proposed as a potential therapeutic target Alzheimer disease (AD). Targeting activity AD requires pharmacological dissociation processing physiological relevant substrates and "toxic" Aβ. Previous reports suggest differential targeting complexes, based on their subunit composition, valid strategy. However, little is known about biochemical properties different key questions regarding...
Abstract Deposition of amyloid-β (Aβ) peptides in the brain is a hallmark Alzheimer’s disease. Aβs are generated through sequential proteolysis amyloid precursor protein by γ-secretase complexes (GSECs). Aβ peptide length, modulated Presenilin (PSEN) and APH-1 subunits GSEC, critical for pathogenesis. Despite high relevance, mechanistic understanding Aβ, its modulation APH-1, remain incomplete. Here, we report cryo-EM structures human GSEC (PSEN1/APH-1B) reconstituted into lipid nanodiscs...
The structure and function of the γ-secretase proteases are vast interest because their critical roles in cellular disease processes. We established a novel purification protocol for complex that involves conformation complex-specific nanobody, yielding highly pure active enzyme. Using single particle electron microscopy, we analyzed its conformational variability. Under steady state conditions adopts three major conformations, which different overall compactness relative position nicastrin...
γ-Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Enhancer 2 (PEN-2), Anterior Pharynx Defective 1 (APH1) the essential subunits GSECs. Mutations PSEN Amyloid Precursor Protein (APP) cause early-onset AD GSECs successively cut APP generate amyloid-β (Aβ) peptides various lengths. AD-causing mutations destabilize GSEC-APP/Aβ
Sequential proteolysis of the amyloid precursor protein (APP) by γ-secretases generates amyloid-β (Aβ) peptides and defines proportion short-to-long Aβ peptides, which is tightly connected to Alzheimer's disease (AD) pathogenesis. Here, we study mechanism that controls substrate processing peptide length. We found polar interactions established APPC99 ectodomain (ECD), involving but not limited its juxtamembrane region, restrain both extent degree processive cleavage destabilizing...
Abstract Alzheimer's disease (AD) pathogenesis has been linked to the accumulation of longer, aggregation‐prone amyloid β (Aβ) peptides in brain. Γ‐secretases generate Aβ from precursor protein (APP). Γ‐secretase modulators (GSMs) promote generation shorter, less‐amyloidogenic Aβs and have therapeutic potential. However, poorly defined drug–target interactions mechanisms action hampered their development. Here, we investigate between imidazole‐based GSM its target γ‐secretase—APP using...
ABSTRACT Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity poorly defined. Here, we explored a novel hypothesis for Aβ42 that arises from its proven affinity γ-secretases. We hypothesized reported increases Aβ42, particularly endolysosomal compartment, promote establishment of product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. show human...
Abstract Deposition of amyloid-β (Aβ) peptides in the brain is a hallmark Alzheimer’s disease. Aβs are generated through sequential proteolysis amyloid precursor protein by γ-secretase complexes (GSECs). Aβ peptide length, which modulated Presenilin (PSEN) and APH-1 subunits GSEC, critical for pathogenesis. Despite high relevance, mechanistic understanding Aβ, its modulation APH-1, remain incomplete. Here, we report cryo-EM structures human GSEC (PSEN1/APH-1B) reconstituted into lipid...
Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity poorly defined. Here, we explored a novel hypothesis for Aβ42 that arises from its proven affinity γ-secretases. We hypothesized reported increases Aβ42, particularly endolysosomal compartment, promote establishment of product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. conducted kinetic...
Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity poorly defined.Here, we explored a novel hypothesis for Aβ42 that arises from its proven affinity γ-secretases. We hypothesized reported increases Aβ42, particularly endolysosomal compartment, promote establishment of product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events.We show human...
Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity poorly defined. Here, we explored a novel hypothesis for Aβ42 that arises from its proven affinity γ-secretases. We hypothesized reported increases Aβ42, particularly endolysosomal compartment, promote establishment of product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. conducted kinetic...
Abstract Sequential proteolysis of the amyloid precursor protein (APP) by γ-secretases (GSECs) generates amyloid-β (Aβ) and defines proportion short-to-long Aβ peptides, which is tightly connected to Alzheimer’s disease (AD) pathogenesis. Here, we study mechanism controlling substrate processing GSECs defining product length. We found that polar interactions established APP C99 ectodomain (ECD), involving but not limited its juxtamembrane region, restrain both extent degree GSEC processive...
Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer’s disease (AD). However, molecular cascades underlying their toxicity poorly defined.Here, we explored a novel hypothesis for Aβ42 that arises from its proven affinity γ-secretases. We hypothesized reported increases Aβ42, particularly endolysosomal compartment, promote establishment of product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events.We show human...
Abstract Background Γ‐secretases are proteolytic switches at the membrane regulating multiple signaling cascades. Their dysfunction, resulting in enhanced generation of longer amyloid β (Aβ) peptides from precursor protein (APP), leads to neurodegeneration context Alzheimer’s disease (AD), while their inhibition causes neurodegenerative phenotypes mice and cognitive worsening AD patients treated with γ‐secretase inhibitors. The accumulation Aβ brain is earliest pathological hallmark AD....
γ-Secretase complexes are multimeric intramembrane proteases sequentially cleaving Amyloid Precursor Protein (APP) to generate amyloid β (Aß) peptides of different lengths. γ-Secretases contain Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Enhancer 2 (PEN-2) and Anterior Pharynx Defective 1 (APH1) as essential subunits. Genetics has shown that single mutations, inherited in an autosomal dominant manner, PSEN APP cause early-onset Alzheimer's disease (AD). Our recent research...