Preclinical validation of a potent γ-secretase modulator for Alzheimer's disease prevention.
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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1
Base de datos:
MEDLINE
Asunto principal:
Fenetilaminas
/
Piridazinas
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Transducción de Señal
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Secretasas de la Proteína Precursora del Amiloide
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Enfermedad de Alzheimer
Idioma:
En
Revista:
J Exp Med
Año:
2021
Tipo del documento:
Article