ArticleBiochemistry2014
Soluble γ-secretase modulators selectively inhibit the production of the 42-amino acid amyloid β peptide variant and augment the production of multiple carboxy-truncated amyloid β species.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 49 citations in OpenAlex.
- PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease.Acta neuropathologica communications · 2024Article
- Microbial infection promotes amyloid pathology in a mouse model of Alzheimer's disease via modulating γ-secretase.Molecular psychiatry · 2024Article
- Review
- PS1/gamma-secretase acts as rogue chaperone of glutamate transporter EAAT2/GLT-1 in Alzheimer's disease.Research square · 2023Article
- A Photolabile Curcumin-Diazirine Analogue Enables Phototherapy with Physically and Molecularly Produced Light for Alzheimer's Disease Treatment.Angewandte Chemie (International ed. in English) · 2023Article
- Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2022Article
- Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2022Article
- Prenatal and Postnatal Pharmacotherapy in Down Syndrome: The Search to Prevent or Ameliorate Neurodevelopmental and Neurodegenerative Disorders.Annual review of pharmacology and toxicology · 2022Article
- Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.The Journal of experimental medicine · 2021Article
- Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates.The Journal of experimental medicine · 2020Article
- Article
- Recent developments of small molecule γ-secretase modulators for Alzheimer's disease.RSC medicinal chemistry · 2020Review
- Dynamic Nature of presenilin1/γ-Secretase: Implication for Alzheimer's Disease Pathogenesis.Molecular neurobiology · 2018Review
- Cromolyn Reduces Levels of the Alzheimer's Disease-Associated Amyloid β-Protein by Promoting Microglial Phagocytosis.Scientific reports · 2018Article
- Short Aβ peptides attenuate Aβ42 toxicity in vivo.The Journal of experimental medicine · 2018Article
- Article
- Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1.EBioMedicine · 2017Article
- Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPScientific reports · 2017Article
- Pharmacological and Toxicological Properties of the Potent OralThe Journal of pharmacology and experimental therapeutics · 2017Article
- Chronic treatment with a smart antioxidative nanoparticle for inhibition of amyloid plaque propagation in Tg2576 mouse model of Alzheimer's disease.Scientific reports · 2017Article
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Authors and funding
11 authors at 5 institutions in 1 country.
Funding
Abstract
Alzheimer's disease (AD) is characterized pathologically by an abundance of extracellular neuritic plaques composed primarily of the 42-amino acid amyloid β peptide variant (Aβ42). In the majority of familial AD (FAD) cases, e.g., those harboring mutations in presenilin 1 (PS1), there is a relative increase in the levels of Aβ42 compared to the levels of Aβ40. We previously reported the characterization of a series of aminothiazole-bridged aromates termed aryl aminothiazole γ-secretase modulators or AGSMs [Kounnas, M. Z., et al. (2010) Neuron 67, 769-780] and showed their potential for use in the treatment of FAD [Wagner, S. L., et al. (2012) Arch. Neurol. 69, 1255-1258]. Here we describe a series of GSMs with physicochemical properties improved compared to those of AGSMs. Specific heterocycle replacements of the phenyl rings in AGSMs provided potent molecules with improved aqueous solubilities. A number of these soluble γ-secretase modulators (SGSMs) potently lowered Aβ42 levels without inhibiting proteolysis of Notch or causing accumulation of amyloid precursor protein carboxy-terminal fragments, even at concentrations approximately 1000-fold greater than their IC50 values for reducing Aβ42 levels. The effects of one potent SGSM on Aβ peptide production were verified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, showing enhanced production of a number of carboxy-truncated Aβ species. This SGSM also inhibited Aβ42 peptide production in a highly purified reconstituted γ-secretase in vitro assay system and retained the ability to modulate γ-secretase-mediated proteolysis in a stably transfected cell culture model overexpressing a human PS1 mutation validating the potential for use in FAD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.