A5056375133- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- Peptidase Inhibition and Analysis
- Cellular transport and secretion
- Nuclear Receptors and Signaling
- Neuroinflammation and Neurodegeneration Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Supramolecular Self-Assembly in Materials
- Protein Structure and Dynamics
- S100 Proteins and Annexins
- Chemical Synthesis and Analysis
- Lipid Membrane Structure and Behavior
- Neurological Disease Mechanisms and Treatments
- Parkinson's Disease Mechanisms and Treatments
- Developmental Biology and Gene Regulation
- Virology and Viral Diseases
- Glycosylation and Glycoproteins Research
- Enzyme Production and Characterization
- Autophagy in Disease and Therapy
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Biochemical and Structural Characterization
- Protein Hydrolysis and Bioactive Peptides
- Microtubule and mitosis dynamics
National Center for Geriatrics and Gerontology
2018-2023
Osaka University
2007-2023
Osaka University of Pharmaceutical Sciences
2021-2023
German Center for Neurodegenerative Diseases
2009-2019
Ludwig-Maximilians-Universität München
2006-2016
Center for Integrated Protein Science Munich
2007-2009
Roche (Switzerland)
2009
LMU Klinikum
2008
Report30 August 2017Open Access Source DataTransparent process An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding phagocytic function Kai Schlepckow Biomedical Center (BMC), Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany Search for more papers by this author Gernot Kleinberger orcid.org/0000-0002-5811-8226 Munich Cluster Systems Neurology (SyNergy), Akio Fukumori German Neurodegenerative Diseases (DZNE) Regina Feederle Helmholtz...
Alzheimer disease amyloid beta-peptide (Abeta) is generated via proteolytic processing of the beta-amyloid precursor protein by beta- and gamma-secretase. Gamma-secretase can be blocked selective inhibitors but also modulated a subset non-steroidal anti-inflammatory drugs, including sulindac sulfide. These drugs selectively reduce generation aggregation-prone 42-amino acid Abeta(42) concomitantly increase levels rather benign Abeta(38). Here we show that Abeta(38) occur independently from...
Intramembrane proteolysis by presenilin-dependent gamma-secretase produces the Notch intracellular cytoplasmic domain (NCID) and Alzheimer disease-associated amyloid-beta. Here, we show that upon signaling of Notch-1 is cleaved into two distinct types NICD species due to diversity in site S3 cleavage. Consistent with N-end rule, S3-V cleavage stable Val at N terminus, whereas S3-S/S3-L generates unstable Ser/Leu terminus. Moreover, signal transmission NICDs much weaker than NICD....
Presenilin (PS1 or PS2) is the catalytic component of γ-secretase complex, which mediates final proteolytic processing step leading to Alzheimer9s disease (AD)-characterizing amyloid β-peptide. PS cleaved during complex assembly into its characteristic N- and C-terminal fragments. Both fragments are integral components physiologically active harbor two critical aspartyl residues site domain. While minimal subunit composition has been defined numerous substrates were identified, cellular...
Pathogenic generation of amyloid β-peptide (Aβ) by sequential cleavage β-amyloid precursor protein (APP) β- and γ-secretases is widely believed to causally underlie Alzheimer disease (AD). β-Secretase initially cleaves APP thereby generating a membrane-bound C-terminal fragment, from which γ-secretase subsequently liberates 37–43-amino acid long Aβ species. Although the latter cleavages are intramembranous although lipid alterations have been implicated in AD, little known how...
As stated by the prevailing amyloid cascade hypothesis, Alzheimer's disease (AD) is caused aggregation and cerebral deposition of long amyloid-β peptide (Aβ) species, which are released from a C-terminal precursor protein fragment γ-secretase. Mutations in its catalytic subunit presenilin-1 (PS1) increase Aβ42 to Aβ40 ratio major cause familial AD (FAD). An opposing hypothesis states that loss essential presenilin functions underlies disease. A argument for this observation nearly inactive...
The canonical pathway of Notch signaling is mediated by regulated intramembrane proteolysis (RIP). In the pathway, ligand binding results in sequential receptor, and presenilin (PS)-dependent at interface between membrane cytosol liberates Notch-1 intracellular domain (NICD), a transcription modifier. Because degradation transmembrane thought to require an additional cleavage near middle domain, extracellular small peptides (Notch-1 Abeta-like peptide (Nbeta)) should be produced. Here we...
γ-Secretase is a unique intramembrane-cleaving protease complex, which cleaves the Alzheimer′s disease-associated β-amyloid precursor protein (APP) and number of other type I membrane proteins. Human γ-secretase consists catalytic subunit presenilin (PS) (PS1 or PS2), substrate receptor nicastrin, APH-1 (APH-1a APH-1b), PEN-2. To facilitate in-depth biochemical analysis γ-secretase, we developed fast convenient multistep purification procedure for endogenous enzyme. The enzyme was purified...
γ-secretase inhibitors (GSI) are drugs developed to decrease amyloid-β peptide (Aβ) production by inhibiting intramembranous cleavage of β-amyloid protein precursor (βAPP). However, a large phase 3 trial semagacestat, potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer's disease (AD) was terminated due unexpected aggravation cognitive deficits and side effects. Here, we show that some semagacestat effects clearly different from phenotype caused loss function...
The presenilin (PS)/γ-secretase complex, which contains not only PS but also Aph-1, PEN-2, and nicastrin, mediates proteolysis of the transmembrane domain β-amyloid protein precursor (βAPP). Intramembrane occurs at interface between membrane cytosol (ε-site) near middle (γ-site), generating βAPP intracellular (AICD) Alzheimer disease-associated Aβ, respectively. Both cleavage sites exhibit some diversity. Changes in precision γ-cleavage, potentially results secretion pathogenic Aβ42, have...
Pathogenic generation of the 42-amino acid variant amyloid beta-peptide (Abeta) by beta- and gamma-secretase cleavage beta-amyloid precursor protein (APP) is believed to be causative for Alzheimer disease (AD). Lowering Abeta(42) production modulators (GSMs) a hopeful approach toward AD treatment. The mechanism GSM action not fully understood. Moreover, whether GSMs target Abeta domain controversial. To further our understanding mode gamma-secretase, we analyzed mutations located at...
Numerous membrane-bound proteins undergo regulated intramembrane proteolysis. Regulated proteolysis is initiated by shedding, and the remaining stubs are further processed intramembrane-cleaving proteases (I-CLiPs). Neuregulin 1 type III (NRG1 III) a major physiological substrate of β-secretase (β-site amyloid precursor protein-cleaving enzyme (BACE1)). BACE1-mediated cleavage required to allow signaling NRG1 III. Because hairpin nature III, two with 2 orientation generated proteolytic...
Sequential processing of the β-amyloid precursor protein by β- and γ-secretase generates amyloid β-peptide (Aβ), which is widely believed to play a causative role in Alzheimer disease. Selective lowering pathogenic 42-amino acid variant Aβ modulators (GSMs) promising therapeutic strategy. Here we report that mutations presenilin (PS), catalytic subunit γ-secretase, display differential responses non-steroidal anti-inflammatory drug (NSAID)-type GSMs more potent second-generation compounds....
Signal peptide peptidase (SPP), its homologs, the SPP-like proteases SPPL2a/b/c and SPPL3, as well presenilin, catalytic subunit of γ-secretase complex, are intramembrane-cleaving aspartyl GxGD type. In this study, we identified 18-kDa leader (LP18) foamy virus envelope protein (FVenv) a new substrate for intramembrane proteolysis by human SPPL3 SPPL2a/b. contrast to SPPL2a/b γ-secretase, which require substrates with an ectodomain shorter than 60 amino acids efficient proteolysis, cleaves...
The lectin-like oxidized LDL receptor 1 (LOX-1) is a key player in the development of atherosclerosis. LOX-1 promotes endothelial activation and dysfunction by mediating uptake inducing pro-atherogenic signaling. However, little known about modulators LOX-1–mediated responses. Here, we show that function controlled proteolytically. Ectodomain shedding metalloprotease ADAM10 lysosomal degradation generate membrane-bound N-terminal fragments (NTFs), which identified as novel substrates...
Introduction Although diabetes and apolipoprotein E (apoE) are both significant risk factors for dementia, including Alzheimer's disease, it remains to be clarified how they related each other in contributing the of dementia. Methods By reviewing National Coordinating Center (NACC) clinical records, we investigated whether affects cognitive decline depending on APOE genotype their potential relationships with neuropathology. Results A interaction between exists, where affected APOE3 carriers...
Abstract Abnormal generation of neurotoxic amyloid‐β peptide (Aβ) 42/43 species due to mutations in the catalytic presenilin 1 ( PS 1) subunit γ‐secretase is major cause familial Alzheimer's disease FAD ). Deeper mechanistic insight on Aβ43 still lacking, and it unclear whether modulators GSM s) can reduce levels this Aβ species. By comparing several types Aβ43‐generating mutants, we observe that very high are often produced when function severely impaired. Altered interactions C99,...