A5066666154- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Cholinesterase and Neurodegenerative Diseases
- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Computational Drug Discovery Methods
- Mitochondrial Function and Pathology
- Adipose Tissue and Metabolism
- Drug Transport and Resistance Mechanisms
- Nuclear Receptors and Signaling
- Parkinson's Disease Mechanisms and Treatments
- Receptor Mechanisms and Signaling
- Cholesterol and Lipid Metabolism
- Metabolism and Genetic Disorders
- 14-3-3 protein interactions
- Ubiquitin and proteasome pathways
- Genetic Neurodegenerative Diseases
- SARS-CoV-2 and COVID-19 Research
- Genetics and Neurodevelopmental Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Diet and metabolism studies
- Glycosylation and Glycoproteins Research
- Hormonal Regulation and Hypertension
- Glycogen Storage Diseases and Myoclonus
- Liver Disease and Transplantation
University of Massachusetts Amherst
2018-2024
Johnson & Wales University
2008-2020
Bread for the World Institute
2020
Forma Therapeutics (United States)
2018
Princeton University
2005-2013
Proteostasis Therapeutics (United States)
2010-2013
KU Leuven
2012
Pfizer (United States)
2010
Duke University
1994-2010
Duke Medical Center
1994-2004
Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and models, there increasing evidence that neuronal dysfunction occurs before the accumulation of β-amyloid (Aβ)-containing plaques neurodegeneration. Characterization timing nature preplaque important understanding progression this to identify pathways molecular targets therapeutic intervention. Hence, we examined at morphological, functional,...
Inheritance of the apoE4 allele (ε4) increases risk developing Alzheimer's disease; however, mechanisms underlying this association remain elusive. Recent data suggest that inheritance ε4 may lead to reduced apoE protein levels in CNS. We therefore examined brains, CSF and plasma ε2/2, ε3/3, ε4/4 targeted replacement mice. These mice showed a genotype-dependent decrease levels; ε2/2 >ε3/3 >ε4/4. Next, we sought examine relative contributions apoE3 ε3/4 mouse brains. ApoE4 represented...
The cerebellum is important for many aspects of behaviour, from posture maintenance and goal-oriented reaching movements to timing tasks certain forms learning. In every case, information flowing through the passes Purkinje neurons, which receive input two primary cerebellar afferents generate continuous streams action potentials that constitute sole output cortex deep nuclei. tonic firing behaviour observed in neurons vivo maintained brain slices even when synaptic inputs are blocked,...
Transcriptional dysregulation by mutant huntingtin (Htt) protein has been implicated in the pathogenesis of Huntington's disease (HD). We find that cultured cells expressing Htt and striatal from HD transgenic mice have elevated nuclear factor-κB (NF-κB) activity. Furthermore, NF-κB is concentrated nucleus neurons brains mice. In inducible PC12 mice, activates IκB kinase complex (IKK), a key regulator NF-κB. Activation IKK likely mediated direct interaction with Htt, because expanded...
The cerebellum is important for many aspects of behaviour, from posture maintenance and goal-oriented reaching movements to timing tasks certain forms learning. In every case, information flowing through the passes Purkinje neurons, which receive input two primary cerebellar afferents generate continuous streams action potentials that constitute sole output cortex deep nuclei. tonic firing behaviour observed in neurons vivo maintained brain slices even when synaptic inputs are blocked,...
Modulation of the activity potassium and other ion channels is an essential feature nervous system function. The open probability a large conductance Ca 2+ -activated K + channel from rat brain, incorporated into planar lipid bilayers, increased by addition adenosine triphosphate (ATP) to cytoplasmic side channel. This modulation takes place without protein kinase, requires Mg , mimicked ATP analog that serves as substrate for kinases but not nonhydrolyzable analog. Addition phosphatase 1...
The presenilin containing γ-secretase complex is responsible for the regulated intramembraneous proteolysis of amyloid precursor protein (APP), Notch receptor, and a multitude other substrates. γ-Secretase catalyzes final step in generation Aβ<sub>40</sub> Aβ<sub>42</sub> peptides from APP. Amyloid β-peptides (Aβ peptides) aggregate to form neurotoxic oligomers, senile plaques, congophilic angiopathy, some cardinal pathologies associated with Alzheimer9s disease. Although inhibition this...
Phenylephrine (2.0 microM) induces an alpha 1-receptor-mediated net efflux of Ca2+ from livers fed rats perfused with medium containing physiological concentrations (1.3 mM) Ca2+. The onset (7.1 +/- 0.5 s; n = 16) immediately precedes a stimulation mitochondrial respiration and glycogenolysis. Maximal rates are observed between 35 s 45 after alpha-agonist administration; thereafter the rate decreases, to be no longer detectable 3 min. Within seconds terminating phenylephrine infusion,...
Abstract —Recent evidence suggests that functional diversity of vascular smooth muscle is produced in part by a differential expression ion channels. The aim the present study was to examine role Ca 2+ -activated K + channels (K channels) cell phenotype. We found cells exhibiting contractile function express predominantly large-conductance (≈200 pS) (BK) In contrast, proliferative much smaller conductance (≈32 pS). These are blocked low concentrations charybdotoxin (10 nmol/L) but, unlike BK...
Voltage-dependent large-conductance Ca2+-activated K+ channels (BK channels) are widely expressed in excitable and nonexcitable cells. BK exhibit diverse electrophysiological properties, which attributable part to alternative splicing of their alpha-subunits. currents have been implicated the growth control glial cells, with novel biophysical properties recently characterized human glioma Here we report isolation, cloning, functional characterization (gBK), a splice isoform hSlo, gene that...
We have cloned and expressed a Ca(2+)-activated K+ channel beta-subunit from human brain. The open reading frame encodes 191-amino acid protein possessing significant homology to previously described subunit bovine muscle. gene for this is located on chromosome 5 at band q34 (hslo-beta). There no evidence alternative RNA splicing of product. hslo-beta mRNA abundantly in smooth muscle, but expression levels are low most other tissues, including Brain subregions which relatively high the...
The amyloid hypothesis states that a variety of neurotoxic beta-amyloid (Abeta) species contribute to the pathogenesis Alzheimer's disease. Accordingly, key determinant disease onset and progression is appropriate balance between Abeta production clearance. Enzymes responsible for degradation are not well understood, and, thus far, it has been possible enhance catabolism by pharmacological manipulation. We provide evidence increased after inhibition plasminogen activator inhibitor-1 (PAI-1)...
Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show that modification of rapamycin at the mammalian target (mTOR) binding region yields ligands, WYE-592 and ILS-920, with potent activities in cortical neuronal cultures, efficacy a rodent model for ischemic stroke, significantly reduced Surprisingly, both compounds showed higher selectivity FKBP52 versus FKBP12, contrast to previously ligands. Affinity purification revealed two key proteins,...
Mutations in leucine-rich repeat kinase 2 (LRRK2) comprise the leading cause of autosomal dominant Parkinson's disease, with age onset and symptoms identical to those idiopathic forms disorder. Several these pathogenic mutations are thought affect its activity, so understanding roles LRRK2, modulation activity,may lead novel therapeutic strategies for treating disease. In this study, highly purified, baculovirus-expressed proteins have been used,for first time providing large amounts protein...
A technique for the rapid preparation of mitochondria from rat liver is described. Tissue fractionation performed by a single centrifugation step with discontinuous Percoll density gradient. Total times 5-6 min are achieved using this method. The mitochondrial fraction obtained relatively free contaminating organelles, as judged marker-enzyme activity determinations. Mitochondria isolated Percoll-density-gradient differ differential [Taylor, Prpić, Exton & Bygrave (1980) Biochem. J. 188,...
SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting metabolically labile methyl groups 9 trifluoromethyl afforded more stable analogue 10, had improved vivo potency. Further side chain modification potent begacestat (5), was selected for development treatment of Alzheimer's disease.
BACE1 is the rate-limiting enzyme that cleaves amyloid precursor protein (APP) to produce β peptides accumulate in Alzheimer's disease (AD). BACE1, which elevated AD patients and APP transgenic mice, also β2-subunit of voltage-gated sodium channels (Navβ2). Although increased levels are associated with Navβ2 cleavage patients, whether occurs mice had not yet been examined. Such a finding would be interest because its potential impact on neuronal activity: previous studies demonstrated...
Mutations in LRRK2 (leucine-rich repeat kinase 2) have been identified as major genetic determinants of Parkinson's disease (PD). The most prevalent mutation, G2019S, increases LRRK2's activity, therefore understanding the sites and substrates that phosphorylates is critical to its role aetiology. Since physiological this are unknown, we set out reveal potential targets G2019S by identifying favored phosphorylation motif. A non-biased screen an oriented peptide library elucidated...