A5045957097- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- Glycosylation and Glycoproteins Research
- Cellular transport and secretion
- Neuroinflammation and Neurodegeneration Mechanisms
- Computational Drug Discovery Methods
- Nuclear Receptors and Signaling
- Inflammation biomarkers and pathways
- Peptidase Inhibition and Analysis
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Cell death mechanisms and regulation
- Neurological disorders and treatments
- Trace Elements in Health
- Parkinson's Disease Mechanisms and Treatments
- Pluripotent Stem Cells Research
- Genetics and Neurodevelopmental Disorders
- 14-3-3 protein interactions
- Mitochondrial Function and Pathology
- Metabolomics and Mass Spectrometry Studies
- CRISPR and Genetic Engineering
- Signaling Pathways in Disease
- Metabolism and Genetic Disorders
- Monoclonal and Polyclonal Antibodies Research
- Endoplasmic Reticulum Stress and Disease
Nagasaki University
2013-2025
Japan Science and Technology Agency
2023
National Institutes of Health
2020
Yale University
2020
Harvard University
2020
Rockefeller University
2020
Science and Technology Corporation (United States)
2017
Centre de Recherche en Économie et Statistique
2017
Centre for Research in Engineering Surface Technology
2017
RIKEN
2001-2013
Amyloid beta peptide (Abeta), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in brain. We examined role neprilysin, candidate Abeta-degrading peptidase, metabolism using neprilysin gene-disrupted mice. Neprilysin deficiency resulted defects both degradation exogenously administered Abeta and metabolic suppression endogenous levels gene dose-dependent manner. The regional neprilysin-deficient mouse brain were distinct order hippocampus, cortex,...
To identify the amyloid β peptide (Aβ) 1–42-degrading enzyme whose activity is inhibited by thiorphan and phosphoramidon in vivo, we searched for neprilysin (NEP) homologues cloned neprilysin-likepeptidase (NEPLP) α, NEPLP β, γ cDNAs. We expressed NEP, phosphate-regulating gene with homologies to endopeptidases on X chromosome (PEX), NEPLPs, damage-induced neuronal endopeptidase (DINE) 293 cells as 95- 125-kDa proteins found that enzymatic activities of PEX, well those NEP DINE, were...
The deposition of amyloid β-peptide (Aβ) in the brain is closely associated with development Alzheimer's disease. Aβ generated from precursor protein (APP) by sequential action β-secretase (BACE1) and γ-secretase. Although BACE1 distributed among various other tissues, its physiological substrates than APP have yet to be identified. ST6Gal I a sialyltransferase that produces sialylα2,6galactose residue, enzyme secreted out cell after proteolytic cleavage. We report here involved cleavage I,...
A local increase in amyloid-β peptide (Aβ) is closely associated with synaptic dysfunction the brain Alzheimer's disease. Here, we report on catabolic mechanism of Aβ at presynaptic sites. Neprilysin, an Aβ-degrading enzyme, expressed by recombinant adeno-associated viral vector-mediated gene transfer, was axonally transported to sites through afferent projections neuronal circuits. This transfer abolished levels hippocampal formations neprilysin-deficient mice and also reduced young mutant...
Abstract Variants of triggering receptor expressed on myeloid cells 2 (TREM2) are associated with an increased incidence Alzheimer’s disease, as well other neurodegenerative disorders. Using a newly developed, highly sensitive reporter cell model, consisting Jurkat T stably overexpressing gene and encoding TREM2DAP12 fusion protein, we show here that TREM2-dependent signal transduction in response to apoptotic Neuro2a is mediated by aminophospholipid ligands, phosphatidylserine...
The gamma-secretase complex catalyzes the final intramembraneous cleavage of beta-amyloid precursor protein, liberating neurotoxic amyloid beta-peptide implicated in Alzheimer's disease. Apart from catalytic subunit presenilin (PS), three additional subunits, nicastrin, APH-1, and PEN-2, have been identified. In mammals, two PS homologues, PS1 PS2, which are part distinct complexes, exist. Likewise, APH-1 APH-1a APH-1b, Furthermore, splice forms, APH-1aS APH-1aL, reported. Here we show that...
Enzymatic proteolysis has been implicated in diverse neuropathological conditions, including acute/subacute ischemic brain injuries and chronic neurodegeneration such as Alzheimer disease Parkinson disease. Calcium-dependent proteases, calpains, have intensively analyzed relation to these pathological but vivo experiments hampered by the lack of appropriate experimental systems for a selective regulation calpain activity animals. Here we generated transgenic (Tg) mice that overexpress human...
γ-Secretase is a protease complex composed of presenilin (PS), nicastrin (NCT), APH-1, and PEN-2, which catalyzes intramembrane cleavage several type I transmembrane proteins including the Alzheimer's disease-associated β-amyloid precursor protein. We generated stable RNA interference-mediated PEN-2 knockdown cells to probe mutant variants for functional activity. Knockdown was associated with impaired NCT maturation deficient PS1 endoproteolysis, efficiently rescued by wild or N-terminally...
Abstract Mutations of proline-rich transmembrane protein 2 (PRRT2) lead to dyskinetic and convulsive disorders such as paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile seizure hemiplegic migraine. PKD is characterized by attacks involuntary movements precipitated suddenly initiated motion. Previous studies have shown that might be caused cerebellar dysfunction; however, considering widespread expression Prrt2 in the whole brain, it likely some other motor-related regions...
Journal Article Biochemical Identification of the Neutral Endopeptidase Family Member Responsible for Catabolism Amyloid β Peptide in Brain Get access Yoshie Takaki, Takaki *Laboratory Proteolytic Neuroscience, RIKEN Science InstituteWako, Saitama 351-0198 Search other works by this author on: Oxford Academic PubMed Google Scholar Nobuhisa Iwata, Iwata Satoshi Tsubuki, Tsubuki Sayuri Taniguchi, Taniguchi 351-0198†Department Biochemistry, Faculty Pharmaceutical Sciences, Hoshi...
γ-Secretase is a high molecular weight multicomponent protein complex with an unusual intramembrane-cleaving aspartyl protease activity. intimately associated Alzheimer disease because it catalyzes the proteolytic cleavage, which leads to liberation of amyloid औ-peptide. At least presenilin (PS), Nicastrin (Nct), APH-1, and PEN-2 are constituents γ-secretase complex, PS apparently providing active site γ-secretase. Expression components tightly regulated, however little known about assembly...
Journal Article Clearance of Extracellular and Cell-Associated Amyloid β Peptide through Viral Expression Neprilysin in Primary Neurons Get access Emi Hama, Hama *Laboratory for Proteolytic Neuroscience, RIKEN Brain Science InstituteWako, Saitama 351-0198 Search other works by this author on: Oxford Academic PubMed Google Scholar Keiro Shirotani, Shirotani Hajime Masumoto, Masumoto Yoko Sekine-Aizawa, Sekine-Aizawa 351-0198†Department Johns Hopkins University School MedicineBaltimore, MD...
Abstract γ‐Secretase is a high molecular mass aspartyl protease complex composed of presenilin (PS1 or PS2), nicastrin (Nct), anterior pharynx‐defective‐1 (APH‐1) and enhancer‐2 (PEN‐2). The mediates the intramembraneous proteolysis β‐secretase cleaved β‐amyloid precursor protein (APP) leading to secretion Alzheimer's disease‐associated amyloid β‐peptide (Aβ). In order dissect functionally important domains Nct required for γ‐secretase assembly, maturation, activity we mutated evolutionary...
Two secretases are involved in the generation of amyloid β-peptide, principal component plaques brains Alzheimer's disease patients. While β-secretase is a classical aspartyl protease, γ-secretase activity associated with high molecular weight complex. One complex components, which critically required for nicastrin (NCT). Here we investigate assembly NCT into mutants either lacking entire cytoplasmic tail, and transmembrane domain (TMD), or containing set heterologous TMDs were expressed...
Neprilysin (NEP) is a rate-limiting amyloid β peptide (Aβ)-degrading enzyme in the brain. We demonstrated previously that overexpression of neprilysin primary cortical neurons remarkably decreased not only extracellular but also intracellular Aβ levels. To investigate subcellular compartments where degrades most efficiently, we expressed chimeric proteins containing various compartment-targeting domains neurons. Sec12-NEP, β-galactoside α2,6-sialyltransferase-NEP, transferrin receptor-NEP,...
Presenilin 2 (PS2) is a polytopic membrane protein that mutated in some cases of familial Alzheimer's disease (AD). The normal functions PS2 and its pathogenic role AD remain unclear. We investigated the biological this neurons, using adenovirus‐mediated transduction gene into rat primary cortical neurons. Immunocytochemical analyses demonstrated increased immunoreactivity most neurons infected with recombinant adenoviruses expressing PS2. Neurons wild‐type or mutant (N141I) PS2‐expressing...
Amyloid-β peptide (Aβ) accumulation is a triggering event leading to the Alzheimer's disease (AD) pathological cascade. Almost all familial AD-linked gene mutations increase Aβ production and accelerate onset of AD. The Swedish mutation amyloid precursor protein (APP) affects β-secretase activity increases up ca. 6-fold in cultured cells; age around 50. Down syndrome (DS) patients with chromosome 21 trisomy present AD-like pathologies at earlier ages (40s) compared sporadic AD patients,...
Presenilin-2 (PS2) is a gene of unknown function linked with some forms familial Alzheimer's disease. To investigate the biological role PS2 in neurons, we overexpressed primary cortical neurons using recombinant adenoviral vectors. Western blot and immunohistochemical analyses showed enhanced expression proteins infected after infection adenoviruses containing human wild-type or mutant gene. Neuronal survival was decreased by approximately 30% cultures adenovirus expressing either PS2, as...