A5090395755- Alzheimer's disease research and treatments
- Cholesterol and Lipid Metabolism
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Cellular transport and secretion
- Drug Transport and Resistance Mechanisms
- Lipoproteins and Cardiovascular Health
- 14-3-3 protein interactions
- Nuclear Receptors and Signaling
- Animal Nutrition and Physiology
- Probiotics and Fermented Foods
- Gut microbiota and health
- Antibiotic Resistance in Bacteria
- Neuroscience and Neuropharmacology Research
- Prion Diseases and Protein Misfolding
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Peroxisome Proliferator-Activated Receptors
- Hormonal Regulation and Hypertension
- Essential Oils and Antimicrobial Activity
- Cell Adhesion Molecules Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Cell death mechanisms and regulation
- Ion channel regulation and function
- Bioinformatics and Genomic Networks
- Intergenerational Family Dynamics and Caregiving
University of Veterinary Medicine
2020-2025
Budapest University of Technology and Economics
2023-2024
Massachusetts General Hospital
2007-2022
Harvard University
2007-2022
MaineGeneral Medical Center
2004-2022
Magyar Agrár- és Élettudományi Egyetem
2016
Cornell University
1997-2011
Brigham and Women's Hospital
2010
University of Helsinki
2010
Harvard University Press
2001-2009
Most cases of early-onset familial Alzheimer's disease (FAD) are caused by mutations in the genes encoding presenilin 1 (PS1) and PS2 proteins, both which undergo regulated endoproteolytic processing. During apoptosis, PS1 were shown to be cleaved at sites distal their normal cleavage a caspase-3 family protease. In cells expressing containing asparagine-141 FAD mutant, ratio alternative fragments was increased relative wild-type PS2-expressing cells, suggesting potential role for...
In situ hybridization was used to assess total amyloid protein precursor (APP) messenger RNA and the subset of APP mRNA containing Kunitz protease inhibitor (KPI) insert in 11 Alzheimer's disease (AD) 7 control brains. AD, a significant twofold increase observed nucleus basalis locus ceruleus neurons but not hippocampal subicular neurons, basis pontis, or occipital cortical neurons. The due exclusively an lacking KPI domain. These findings suggest that increased production domain may play...
Brains of patients affected by Alzheimer9s disease (AD) contain large deposits aggregated amyloid β-protein (Aβ). Only a small fraction the precursor protein (APP) gives rise to Aβ. Here, we report that ∼10% APP undergoes post-translational lipid modification called palmitoylation. We identified palmitoylation sites in at Cys<sup>186</sup> and Cys<sup>187</sup>. Surprisingly, point mutations introduced into these cysteines caused nearly complete ER retention APP. Thus, either or disulfide...
Pathogenic mutations in presenilin 1 (PS1) are associated with ≈50% of early-onset familial Alzheimer disease. PS1 is endoproteolytically cleaved to yield a 30-kDa N-terminal fragment (NTF) and an 18-kDa C-terminal (CTF). Using COS7 cells transfected human PS1, we have found that phorbol 12,13-dibutyrate forskolin increase the state phosphorylation serine residues CTF. Phosphorylation CTF resulted shift electrophoretic mobility from single major species 18 kDa doublet 20–23 kDa. This was...
The abnormal accumulation of amyloid beta-peptide (Abeta) in the form senile (or amyloid) plaques is one main characteristics Alzheimer disease (AD). Both cholesterol and Cu2+ have been implicated AD pathogenesis plaque formation. Abeta binds with very high affinity, forming a redox-active complex that catalyzes H2O2 production from O2 cholesterol. Here we show Abeta:Cu2+ complexes oxidize selectively at C-3 hydroxyl group, catalytically producing 4-cholesten-3-one therefore mimicking...
Alzheimer disease-associated beta-amyloid peptide is generated from its precursor protein APP. By using the yeast two-hybrid assay, here we identified HtrA2/Omi, a stress-responsive chaperone-protease as binding to N-terminal cysteinerich region of HtrA2 coimmunoprecipitates exclusively with immature APP cell lysates well mouse brain extracts and degrades in vitro. A subpopulation localizes cytosolic side endoplasmic reticulum (ER) membrane where it contributes ER-associated degradation...
Cerebral accumulation of amyloid-β (Aβ) is characteristic Alzheimer disease and amyloid precursor protein (APP) transgenic mice. Here, we assessed the efficacy CI-1011, an inhibitor acyl-coenzyme A:cholesterol acyltransferase, which suitable for clinical use, in reducing pathology both young (6.5 months old) aged (16 human APP Treatment animals with CI-1011 decreased plaque load cortex hippocampus reduced levels insoluble Aβ40 Aβ42 C-terminal fragments brain extracts. In mice, specifically...
Although BACE1 is a major therapeutic target for Alzheimer's disease (AD), potential side effects of inhibition are not well characterized. cleaves over 60 putative substrates, however the majority these cleavages have been Here we investigated BACE1-mediated cleavage human contactin-2, GPI-anchored cell adhesion molecule. Our initial protein sequence analysis showed that contactin-2 harbors strong site close to its GPI membrane linker domain. When overexpressed in CHO cells stably...
BACE1 and presenilin (PS)/γ-secretase play a major role in Alzheimer's disease pathogenesis by regulating amyloid-β peptide generation. We recently showed that these secretases also regulate the processing of voltage-gated sodium channel auxiliary β-subunits thereby modulate membrane excitability. Here, we report KCNE1 KCNE2, subunits potassium channels, undergo sequential cleavage mediated either α-secretase PS/γ-secretase or cells. Elevated activities increased C-terminal fragment (CTF)...
Accumulation of the β-amyloid peptide (Aβ) is a major pathological hallmark Alzheimer's disease (AD). Recent studies have shown that synaptic Aβ toxicity may directly impair function. However, proteins regulating generation at synapse not been characterized. Here, we sought to identify interact with extracellular domain APP and regulate generation. Affinity purification-coupled mass spectrometry identified members Synaptotagmin (Syt) family as novel interacting ectodomain in mouse brains....
Previous studies have shown that acyl‐coenzyme A:cholesterol acyl transferase (ACAT), an enzyme controls cellular equilibrium between free cholesterol and cholesteryl esters, modulates proteolytic processing of APP in cell‐based animal models Alzheimer's disease. Here we report ACAT‐1 RNAi reduced protein by ∼50% ester levels 22% while causing a slight increase the content ER membranes. This correlated with 40% decrease Aβ secretion. These data show even modest ACAT activity can robust...
The presenilin (PS)/gamma-secretase complex proteolytically cleaves more than 20 different proteins in addition to the amyloid precursor protein (APP). These substrates are almost exclusively type I membrane proteins. Many undergo internalization from cell surface followed by degradation or recycling back plasma through endocytic compartment (ERC). Evidence shows that PSs also regulate intracellular trafficking of APP and its C-terminal fragments (CTFs). To investigate whether...
Amyloid β-peptide (Aβ) has a central role in the pathogenesis of Alzheimer's disease (AD). Cellular cholesterol homeostasis regulates endoproteo- lytic generation Aβ from amyloid precursor protein (APP). Previous studies have identified acyl- coenzyme A: acyltransferase (ACAT)' an enzyme that subcellular distribu-tion, as potential therapeutic target for AD. Inhibition ACAT activity decreases cell- and animal-based models AD through unknown mechanism. Here we show inhibition retains fraction...
Leukocyte-common antigen-related (LAR) receptor tyrosine phosphatase regulates cell adhesion and formation of functional synapses neuronal networks. Here we report that LAR is sequentially cleaved by alpha- presenilin (PS)/gamma-secretases, which also affect signaling and/or degradation type-I membrane proteins including the Alzheimer disease-related beta-amyloid precursor protein. Similar to previously characterized PS/gamma-secretase substrates, inhibition gamma-secretase activity resulted...
Synaptic loss strongly correlates with memory deterioration. Local accumulation of amyloid β (Aβ) peptide, and neurotoxic Aβ42 in particular, due to abnormal neuronal activity may underlie synaptic dysfunction, neurodegeneration, impairments. To gain an insight into molecular events underlying activity-regulated Aβ production at the synapse, we explored functional outcomes newly discovered calcium-dependent interaction between Alzheimer’s disease-associated presenilin 1 (PS1)/γ-secretase...