A5023581135- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Protease and Inhibitor Mechanisms
- Bioinformatics and Genomic Networks
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Prion Diseases and Protein Misfolding
- Blood Coagulation and Thrombosis Mechanisms
- Nuclear Receptors and Signaling
- Neuroscience and Neuropharmacology Research
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Dementia and Cognitive Impairment Research
- Drug Transport and Resistance Mechanisms
- Epigenetics and DNA Methylation
- Neuroinflammation and Neurodegeneration Mechanisms
- Peptidase Inhibition and Analysis
- Tryptophan and brain disorders
- Parkinson's Disease Mechanisms and Treatments
- Genomics and Chromatin Dynamics
- Supramolecular Self-Assembly in Materials
- Pharmacogenetics and Drug Metabolism
- Enzyme Production and Characterization
- RNA Research and Splicing
- Pluripotent Stem Cells Research
- S100 Proteins and Annexins
University of California, San Diego
2015-2025
VA San Diego Healthcare System
2017-2025
Massachusetts General Hospital
2017-2023
Torrey Pines Institute For Molecular Studies
2005-2010
University of Freiburg
2009
Merck (Japan)
2003-2005
NeuroGenetic Pharmaceuticals (United States)
2004-2005
University of Chicago
2005
Southern Illinois University School of Medicine
2004
Georgetown University Medical Center
1998
Store-operated Ca2+ (SOC) channels regulate many cellular processes, but the underlying molecular components are not well defined. Using an RNA interference (RNAi)-based screen to identify genes that alter thapsigargin (TG)-dependent entry, we discovered a required and conserved role of Stim in SOC influx. RNAi-mediated knockdown Drosophila S2 cells significantly reduced TG-dependent entry. Patch-clamp recording revealed nearly complete suppression release-activated (CRAC) current has...
Amyloid precursor protein (APP) is endoproteolytically processed by BACE1 and γ-secretase to release amyloid peptides (Aβ40 42) that aggregate form senile plaques in the brains of patients with Alzheimer's disease (AD). The C-terminus Aβ40/42 generated γ-secretase, whose activity dependent upon presenilin (PS 1 or 2). Missense mutations PS1 (and PS2) occur early-onset familial AD (FAD), previous studies transgenic mice cultured cell models demonstrated FAD-PS1 variants shift ratio Aβ40 : 42...
Genetic, epidemiologic, and biochemical evidence suggests that predisposition to Alzheimer's disease (AD) may arise from altered cholesterol metabolism, although the molecular pathways link AD phenotypes are only partially understood. Here, we perform a phenotypic screen for pTau accumulation in AD-patient iPSC-derived neurons identify cholesteryl esters (CE), storage product of excess cholesterol, as upstream regulators Tau early during development. Using isogenic induced pluripotent stem...
Susceptibility to Alzheimer's disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor–related protein (LRP) and its ligands, apoE α2M, are all genetically associated with AD. In this study, we provide evidence for involvement of LRP pathway in amyloid deposition through sequestration removal soluble β-protein (Aβ). We demonstrate vitro that mediates clearance both Aβ40 Aβ42 a bona fide receptor-mediated uptake mechanism. vivo, reduced expression genotypes...
Recent analyses suggest that the known Alzheimer's disease genes account for less than half genetic variance in this disease. The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate located near a well-established linkage peak on chromosome 9q22.We evaluated 19 single-nucleotide polymorphisms three within 9q region 437 multiplex families with from National Institute Mental Health (NIMH) sample (1439 subjects). We then tested showing positive result an independently identified set...
ADAM10, a member of disintegrin and metalloprotease family, is an α-secretase capable anti-amyloidogenic proteolysis the amyloid precursor protein. Here, we present evidence for genetic association ADAM10 with Alzheimer's disease (AD) as well two rare potentially disease-associated non-synonymous mutations, Q170H R181G, in prodomain. These mutations were found 11 16 affected individuals (average onset age 69.5 years) from seven late-onset AD families. Each mutation was also one unaffected...
The amyloid beta-protein is deposited in senile plaques and the cerebrovasculature Alzheimer disease (AD). Since it derived from proteolytic processing of its parent protein, precursor (APP), we investigated whether levels secreted forms APP are altered cerebrospinal fluid (CSF) AD patients. Quantitative immunoblotting studies with anti-APP monoclonal antibody P2-1 revealed that probable patients had markedly lower CSF than did demented non-Alzheimer-type healthy control subjects. Using an...
Cognitive deficits in mice with a Down syndrome–like genetic defect can be reversed precursors to the neurotransmitter norepinephrine.
Abstract The relationship between amyloid-β (Aβ) species and tau pathology in Alzheimer’s disease (AD) is not fully understood. Here, we provide direct evidence that Aβ42/40 ratio, total Aβ level, plays a critical role inducing neurofibrillary tangles (NTFs) human neurons. Using 3D-differentiated clonal neural progenitor cells (hNPCs) expressing varying levels of amyloid β precursor protein (APP) presenilin 1 (PS1) with AD mutations, show pathogenic accumulation aggregation are tightly...
Protease nexin-2 (PN-2) is a protease inhibitor that synthesized and secreted by variety of extravascular cells including human fibroblasts. It forms sodium dodecyl sulfate-stable complexes with trypsin, the epidermal growth factor binding protein gamma-subunit nerve factor. Recently we reported PN-2 form amyloid beta-protein precursor (APP) potent chymotrypsin. Here describe two-step procedure to purify PN-2/APP using monoclonal antibody immunoaffinity column. We also quantitated inhibitory...
Protease nexin-1 (PN-1) is a cell-secreted protein that inhibits certain proteases, particularly thrombin, by forming SDS-stable complexes with the catalytic site serine of protease. PN-1 was recently shown to be identical glial-derived neurite-promoting factor/glial-derived nexin present in rat brain. Its neurite outgrowth activity depends on inhibition presumably because thrombin brings about retraction. Here we show human brain contains and brains individuals Alzheimer disease (AD) only...
Ectopic cell cycle events (CCEs) mark vulnerable neuronal populations in human Alzheimer disease (AD) and are observed early progression. In transgenic mouse models of AD, CCEs found before the onset beta-amyloid peptide (Abeta) deposition to form senile plaques, a hallmark AD. Here, we have demonstrated that alterations brain microglia occur coincidently with appearance R1.40 model Furthermore, promotion inflammation LPS at young ages mice induced CCEs, whereas treatment 2 different...
Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or safety concerns. One potential shortcoming current approaches disease discovery and development is that they rely primarily on transformed cell lines animal models substantially overexpress wild-type mutant proteins. It possible failures thus far are caused in part by limits these approaches, which do not accurately reveal how will behave...
Neurons in familial Alzheimer’s disease undergo dedifferentiation, resulting loss of lineage state and degeneration.
A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with inhibitors (GSIs) and potentially enable use in primary prevention of early-onset familial Alzheimer’s disease (EOFAD). Unlike GSIs, GSMs do not inhibit activity but rather allosterically modulate γ-secretase, reducing the net production Aβ42 a lesser extent Aβ40, while concomitantly augmenting Aβ38 Aβ37. This GSM demonstrated robust time- dose-dependent efficacy acute, subchronic, chronic studies...