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Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.
Rynearson, Kevin D; Ponnusamy, Moorthi; Prikhodko, Olga; Xie, Yuhuan; Zhang, Can; Nguyen, Phuong; Hug, Brenda; Sawa, Mariko; Becker, Ann; Spencer, Brian; Florio, Jazmin; Mante, Michael; Salehi, Bahar; Arias, Carlos; Galasko, Douglas; Head, Brian P; Johnson, Graham; Lin, Jiunn H; Duddy, Steven K; Rissman, Robert A; Mobley, William C; Thinakaran, Gopal; Tanzi, Rudolph E; Wagner, Steven L.
Afiliación
  • Rynearson KD; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Ponnusamy M; Department of Molecular Medicine and Byrd Alzheimer's Institute, University of South Florida, Morsani College of Medicine, Tampa, FL.
  • Prikhodko O; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Xie Y; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Zhang C; Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA.
  • Nguyen P; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Hug B; Veterans Administration San Diego Healthcare System, La Jolla, CA.
  • Sawa M; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Becker A; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Spencer B; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Florio J; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Mante M; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Salehi B; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Arias C; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Galasko D; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Head BP; Veterans Administration San Diego Healthcare System, La Jolla, CA.
  • Johnson G; Department of Anesthesiology, University of California, San Diego, La Jolla, CA.
  • Lin JH; NuPharmAdvise, Sanbornton, NH.
  • Duddy SK; Biopharm Consulting Partners, Ambler, PA.
  • Rissman RA; Integrated Nonclinical Development Solutions, Ann Arbor, MI.
  • Mobley WC; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Thinakaran G; Veterans Administration San Diego Healthcare System, La Jolla, CA.
  • Tanzi RE; Department of Neurosciences, University of California, San Diego, La Jolla, CA.
  • Wagner SL; Department of Molecular Medicine and Byrd Alzheimer's Institute, University of South Florida, Morsani College of Medicine, Tampa, FL.
J Exp Med ; 218(4)2021 04 05.
Article en En | MEDLINE | ID: mdl-33651103
ABSTRACT
A potent γ-secretase modulator (GSM) has been developed to circumvent problems associated with γ-secretase inhibitors (GSIs) and to potentially enable use in primary prevention of early-onset familial Alzheimer's disease (EOFAD). Unlike GSIs, GSMs do not inhibit γ-secretase activity but rather allosterically modulate γ-secretase, reducing the net production of Aß42 and to a lesser extent Aß40, while concomitantly augmenting production of Aß38 and Aß37. This GSM demonstrated robust time- and dose-dependent efficacy in acute, subchronic, and chronic studies across multiple species, including primary and secondary prevention studies in a transgenic mouse model. The GSM displayed a >40-fold safety margin in rats based on a comparison of the systemic exposure (AUC) at the no observed adverse effect level (NOAEL) to the 50% effective AUC or AUCeffective, the systemic exposure required for reducing levels of Aß42 in rat brain by 50%.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fenetilaminas / Piridazinas / Transducción de Señal / Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer Idioma: En Revista: J Exp Med Año: 2021 Tipo del documento: Article
Texto completo
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PubMed Links
Buscar en Google

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Fenetilaminas / Piridazinas / Transducción de Señal / Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer Idioma: En Revista: J Exp Med Año: 2021 Tipo del documento: Article