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Aß oligomers induce pathophysiological mGluR5 signaling in Alzheimer's disease model mice in a sex-selective manner.
Abd-Elrahman, Khaled S; Albaker, Awatif; de Souza, Jessica M; Ribeiro, Fabiola M; Schlossmacher, Michael G; Tiberi, Mario; Hamilton, Alison; Ferguson, Stephen S G.
Afiliación
  • Abd-Elrahman KS; University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H 8M5, Canada.
  • Albaker A; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
  • de Souza JM; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
  • Ribeiro FM; University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H 8M5, Canada.
  • Schlossmacher MG; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
  • Tiberi M; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 12371, Saudi Arabia.
  • Hamilton A; University of Ottawa Brain and Mind Research Institute, Ottawa, Ontario K1H 8M5, Canada.
  • Ferguson SSG; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Sci Signal ; 13(662)2020 12 15.
Article en En | MEDLINE | ID: mdl-33323410
The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although ß-amyloid (Aß) deposition is a pathological hallmark of AD in both sexes. Aß-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, we found that mGluR5 exhibits distinct sex-dependent profiles. Specifically, mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aß oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aß-mGluR5 interaction did not appear to depend on estrogen, but rather Aß interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aß oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aß pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aß oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. Our findings indicate that mGluR5 does not contribute to Aß pathology in females, highlighting the complexity of mGluR5 pharmacology and Aß signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Corteza Cerebral / Péptidos beta-Amiloides / Caracteres Sexuales / Multimerización de Proteína / Enfermedad de Alzheimer / Receptor del Glutamato Metabotropico 5 Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Corteza Cerebral / Péptidos beta-Amiloides / Caracteres Sexuales / Multimerización de Proteína / Enfermedad de Alzheimer / Receptor del Glutamato Metabotropico 5 Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos