Caspases, effectors of apoptosis, are key mediators of neuronal death in several neurodegenerative diseases. Caspase-8 and caspase-6 have been implicated in the pathogenesis of amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and Alzheimer's disease (AD). ß-Amyloid precursor protein (APP) is cleaved at Asp664 in its intracellular domain by caspase-8. We and other laboratories recently showed that obliteration of the caspase cleavage site on APP alleviates functional AD-like deficits in a mouse model. Therefore, caspase cleavage of APP constitutes a potential novel target for therapeutic intervention. To identify chemical inhibitors of caspase-8 cleavage, we screened a subset of the chemical library at the Harvard NeuroDiscovery Center's Laboratory for Drug Discovery in Neurodegeneration. We show that caspase-8, but not caspase-1, -3, or -9, cleaves a biotinylated peptide derived from APP at Asp664, and we report the development of a sensitive high-throughput assay for caspase-8 cleavage of APP and the use of that assay for the identification of specific small molecule "hit" compounds that potently inhibit Asp664 cleavage of APP. Furthermore, we demonstrate that one of these compounds (LDN-0021835) inhibits the cleavage of APP at Asp664 in cell-based assays.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.ab.2011.11.020 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
New lanthanum (III) complexes containing azaphosphor β-diketon and diimine ligands: Synthesis, crystallography, morphology properties, DNA binding, DNA cleavage, and DFT calculation.
Int J Biol Macromol
December 2024
Faculty of Chemistry and Mineralogy, Universität Leipzig, Johannisallee 29, Leipzig 04103, Germany.
Two octa-coordinated lanthanum (III) complexes of deprotonated azaphosphor β-diketon and diimine ligands, [LnLQ] (L = [ClCHC(O)NP(O)(NCH)], Q = Phen (C1) and Bipy (C2)), were synthesized and characterized by elemental analysis, IR, and NMR spectra. X-ray crystallography revealed a distorted tetragonal antiprism LaO6N2 coordination geometry around the lanthanum atom in both compounds. Nano-sized complexes (Ć1 and Ć2) were synthesized via a sonochemical process and analyzed using SEM and XRPD.
View Article and Find Full Text PDFUse of a small molecule microarray screen to identify inhibitors of the catalytic RNA subunit of Methanobrevibacter smithii RNase P.
Nucleic Acids Res
December 2024
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
Despite interest in developing therapeutics that leverage binding pockets in structured RNAs-whose dysregulation leads to diseases-such drug discovery efforts are limited. Here, we have used a small molecule microarray (SMM) screen to find inhibitors of a large ribozyme: the Methanobrevibacter smithii RNase P RNA (Msm RPR, ∼300 nt). The ribonucleoprotein form of RNase P, which catalyzes the 5'-maturation of precursor tRNAs, is a suitable drug target as it is essential, structurally diverse across life domains, and present in low copy.
View Article and Find Full Text PDFEffects and mechanisms of APP and its cleavage product Aβ in the comorbidity of sarcopenia and Alzheimer's disease.
Front Aging Neurosci
November 2024
Institute of Intelligent Sport and Proactive Health, Department of Health and Physical Education, Jianghan University, Wuhan, China.
Sarcopenia and AD are both classic degenerative diseases, and there is growing epidemiological evidence of their comorbidity with aging; however, the mechanisms underlying the biology of their commonality have not yet been thoroughly investigated. APP is a membrane protein that is expressed in tissues and is expressed not only in the nervous system but also in the NMJ and muscle. Deposition of its proteolytic cleavage product, Aβ, has been described as a central component of AD pathogenesis.
View Article and Find Full Text PDFSecretase promotes AD progression: simultaneously cleave Notch and APP.
Front Aging Neurosci
November 2024
Science and Experimental Research Center of Shenyang Medical College, Shenyang, Liaoning, China.
Article Synopsis
- Alzheimer's disease (AD) is linked to secretases, which are enzymes that cleave proteins, playing a vital role in regulating key factors like amyloid precursor protein (APP) and Notch that influence both AD and cancer.
- The article details the functions, cleavage sites, and biological roles of six secretase types (α, β, γ, δ, ε, η) and highlights their similarities and differences in how they interact with APP and Notch to affect disease progression.
- It also discusses the potential of secretase inhibitors as a treatment strategy in AD and cancer, reviewing their chemical structures, current research stages, and future development prospects.
Small molecule inhibits BACE1 activity by a dual mechanism confirmed by simulations-based study.
J Biomol Struct Dyn
December 2024
Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
Article Synopsis
- Alzheimer's disease (AD) is a serious neurodegenerative disorder marked by amyloid-beta plaques and neurofibrillary tangles, and it's primarily initiated by the action of the enzyme BACE1 on amyloid precursor protein (APP).
- Researchers have discovered a small molecule that appears to effectively inhibit BACE1 by fitting well into its active site, outperforming the known drug Umibecestat (CNP-520) in terms of binding orientation and blocking the enzyme's activity.
- The study utilized advanced techniques like virtual high-throughput screening and molecular dynamics simulations to identify and analyze potential drug leads for AD treatment, ultimately suggesting a promising new inhibitor for further development.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!