A5107441743- Alzheimer's disease research and treatments
- Computational Drug Discovery Methods
- Cholinesterase and Neurodegenerative Diseases
- Drug Transport and Resistance Mechanisms
- Neuroscience and Neuropharmacology Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Mitochondrial Function and Pathology
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Statistical Methods in Clinical Trials
- Biochemical effects in animals
- Chemical Synthesis and Analysis
- Adipose Tissue and Metabolism
- Machine Learning in Bioinformatics
- Tryptophan and brain disorders
- Neurotransmitter Receptor Influence on Behavior
- Dementia and Cognitive Impairment Research
- Clusterin in disease pathology
- Aluminum toxicity and tolerance in plants and animals
- Genetic Neurodegenerative Diseases
- Nuclear Receptors and Signaling
- Receptor Mechanisms and Signaling
- Retinoids in leukemia and cellular processes
- Protein Kinase Regulation and GTPase Signaling
- S100 Proteins and Annexins
- Lipid Membrane Structure and Behavior
Eli Lilly (United States)
2009-2022
University of Utah
2021
Weatherford College
2009
Washington University in St. Louis
2003-2009
Indiana University – Purdue University Indianapolis
2003-2007
Indiana University School of Medicine
2003-2007
Oregon Health & Science University
2006
University of Rochester Medical Center
2006
Society for Neuroscience
2003
CNS Research (United States)
1996
Converging lines of evidence implicate the beta-amyloid peptide (Ass) as causative in Alzheimer's disease. We describe a novel class compounds that reduce A beta production by functionally inhibiting gamma-secretase, activity responsible for carboxy-terminal cleavage required production. These molecules are active both 293 HEK cells and neuronal cultures, exert their effect upon without affecting protein secretion, most notably secreted forms amyloid precursor (APP). Oral administration one...
According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation initiated when β-secretase (BACE1) cleaves precursor protein. For more than a decade, BACE1 has been prime target designing drugs prevent or treat AD. However, development such agents turned out be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using...
Abstract Objective Accumulation of amyloid‐β (Aβ) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event pathogenesis Alzheimer's disease. However, previously, there has not been method determine drug effects on Aβ production clearance human CNS. The objective this study was γ‐secretase inhibitor Methods We utilized recently developed stable‐isotope labeling combined with cerebrospinal fluid sampling directly measure during treatment...
BACE1 is a key protease controlling the formation of amyloid β, peptide hypothesized to play significant role in pathogenesis Alzheimer's disease (AD). Therefore, development potent and selective inhibitors has been focus many drug discovery efforts academia industry. Herein, we report nonclinical early clinical LY2886721, active site inhibitor that reached phase 2 trials AD. LY2886721 high selectivity against off-target proteases, which efficiently translates vitro activity into robust vivo...
Soluble amyloid-β (Aβ) peptide converts to structures with high β-sheet content in Alzheimer's disease (AD). Aβ is released by neurons into the brain interstitial fluid (ISF), which it can convert toxic aggregates. Because assessment of ISF levels may provide unique insights metabolism and AD, an vivo microdialysis technique was developed measure it. Our validated ex human CSF then awake, freely moving mice. Using amyloid precursor protein (APP) transgenic mice, we found that, before onset...
Amyloid beta peptide (A beta), the major protein constituent of senile plaques in patients with Alzheimer's disease, is believed to facilitate progressive neurodegeneration that occurs latter stages this disease. Early attempts characterize structure-activity relationship A toxicity vitro were compromised by inability reproducibly elicit beta-dependent across different lots chemically equivalent peptides. In study we used CD spectroscopy demonstrate secondary structure an important...
Functional γ-secretase inhibitors (FGSIs) can block the cleavage of several transmembrane proteins including amyloid precursor protein (APP), and cell fate regulator Notch-1. FGSIs, by inhibiting APP processing, generation β (Aβ) peptides may slow development Alzheimer's disease. FGSIs used to inhibit processing disrupt Notch thus interfering with determination. Described herein is a FGSI-mediated gastrointestinal toxicity characterized population changes in ileum rats, which are indicative...
LY450139 dihydrate, a gamma-secretase inhibitor, was studied in randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 5 weeks. Treatment well tolerated. Abeta(1-40) plasma decreased 38.2%; CSF, 4.42 +/- 9.55% (p = not significant). Higher drug doses may result additional decreases Abeta concentrations and measurable decrease CSF Abeta.
A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion highly amyloidogenic, 42-residue amyloid-beta peptide Abeta42. We found that Rho and its effector, Rho-associated kinase, regulated amount Abeta42 produced in vitro only those NSAIDs effective as inhibitors lowered Administration Y-27632, a selective Rock inhibitor, also brain levels transgenic mouse model Alzheimer's disease. Thus, Rho-Rock pathway may regulate amyloid precursor...
Passive immunization with an antibody directed against the N terminus of amyloid beta (Abeta) has recently been reported to exacerbate cerebral angiopathy (CAA)-related microhemorrhage in a transgenic animal model. Although mechanism responsible for deleterious interaction is unclear, direct binding event may be required. We characterized properties several monoclonal anti-Abeta antibodies deposited Abeta brain parenchyma and CAA. Biochemical analyses demonstrated that 3D6 10D5, two...
The gamma-secretase complex plays a role in Alzheimer's disease and cancer progression. development of clinically useful inhibitors, however, is complicated by the regulated intramembrane proteolysis Notch other essential proteins. Different complexes containing different Presenilin or Aph1 protein subunits are present various tissues. Here we show that these have heterogeneous biochemical physiological properties. Specific inactivation Aph1B mouse model led to improvements disease-relevant...
Amyloid β (Aβ) may play a central role in the pathogenesis of Alzheimer disease. A functional γ-secretase inhibitor, LY450139, was developed that inhibits Aβ formation whole cell assays, transgenic mice, and beagle dogs. The authors wished to determine safety tolerability this drug, reduction plasma cerebrospinal fluid (CSF) after multiple doses. Volunteer subjects (N = 37) were studied using doses from 5 50 mg/day given for 14 days. Plasma CSF concentrations Aβ1-40 Aβ1-X ("Aβtotal")...
Objectives: γ-Secretase inhibitors may be useful as disease-modifying drugs for the treatment of Alzheimer disease. LY450139 is a γ-secretase inhibitor currently in clinical development, with doses being optimized through use biomarkers. Methods: To further characterize biomarker responses to LY450139, single oral 60, 100, or 140 mg were administered volunteers without neuropsychiatric Extensive safety assessments obtained along measures changes amyloid-β (Aβ) plasma and cerebrospinal fluid...
Neurodegenerative processes in Alzheimer disease (AD) are thought to be driven part by the deposition of amyloid beta (A beta), a 39- 43-amino acid peptide product resulting from an alternative cleavage precursor protein. Recent descriptions vitro neurotoxic effects A support this hypothesis and suggest toxicity might mediated beta-induced neuronal calcium disregulation. In addition, it has been reported that "aging" results increased toxic potency due aggregation formation beta-sheet...
Abstract Apolipoprotein E (apoE) is an important protein involved in lipoprotein clearance and cholesterol redistribution. ApoE abundantly expressed astrocytes the brain closely linked to pathogenesis of Alzheimer's disease (AD). We report here that small molecule ligands activate either liver X receptors (LXR) or retinoid receptor (RXR) lead a dramatic increase apoE mRNA expression as well secretion human astrocytoma cell line (CCF‐STTG1 cells). Examination primary mouse also revealed...
Abstract Amylin, a 37‐amino‐acid amyloidogenic peptide, bears biophysical similarities to the amyloid‐ β peptide (A ) deposited in Alzheimer's disease. Using embryonic rat hippocampal cultures we tested whether amylin induces neurotoxicity similar that previously observed with A (1–40). Treatment human (1–37) resulted prominent toxicity as assessed by phasecontrast microscopy and quantification of lactate dehydrogenase medium. Amylin‐induced was morphologically induced In contrast,...
Objective:Semagacestat, a γ-secretase inhibitor, demonstrated an unfavorable risk–benefit profile in Phase 3 study of patients with Alzheimer's disease (IDENTITY trials), and clinical development was halted. To assist future inhibitors, we report detailed safety findings from the IDENTITY study, emphasis on those that might be mechanistically linked to inhibition.Research design methods:The trial double-blind, placebo-controlled semagacestat (100 mg 140 mg), which 1537 age 55 years older...
The phosphorylation status of amyloid precursor protein (APP) at Thr668 is suggested to play a critical role in the proteolytic cleavage APP, which generates either soluble APP β (sAPP ) and β‐amyloid peptide (Aβ), major component senile plaques patient brains inflicted with Alzheimer's disease (AD), or α smaller than Aβ. One kinases known phosphorylate cyclin‐dependent kinase 5 (Cdk5). Cdk5 activated by association its regulatory partner p35 truncated form, p25, elevated AD brains....