Divergent Roles of mGlu2 and mGlu3 Receptors in Amyloid‐β Production and Cognitive Dysfunctions in Alzheimer's Disease

Immunotherapy is a promising avenue for reducing amyloid-β (Aβ) accumulation, a hallmark of Alzheimer's disease (AD) pathology. Camelid single domain antibodies, called nanobodies, offer several advantages over conventional monoclonal antibodies, including improved brain penetration and fine-tuning of the targeted neuroreceptors, and may represent an effective strategy to modulate Aβ production. Among potential therapeutic targets, group II metabotropic glutamate receptors (mGluR2 and mGluR3) have been implicated in Aβ regulation, though their individual contributions remain unclear. Here, we showed that activation of mGluR2 significantly increases Aβ peptides and sAPPβ production in a cellular model, by enhancing the internalization of amyloid precursor protein (APP) and its subsequent amyloidogenic processing. In contrast, mGluR3 directly interacts with APP, protecting it from amyloidogenic cleavage and favoring its non-amyloidogenic processing. We used a brain-penetrant nanobody acting as a selective positive allosteric modulator of mGluR2 to validate its role in Aβ dynamics in vivo. Chronic administration of this nanobody in 5xFAD mice accelerated amyloid plaque deposition and worsened cognitive deficits. These findings establish mGluR2 as a target in AD and demonstrate that its selective modulation by nanobodies influences Aβ pathology. This also highlights the potential of nanobodies as next-generation therapeutic agents for modulating neuroreceptors activity in AD.

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Publication Details

Journal
Advanced Science
Published
2026-04-14
DOI
https://doi.org/10.1002/advs.202523791
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
0.00

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article

Divergent Roles of mGlu2 and mGlu3 Receptors in Amyloid‐β Production and Cognitive Dysfunctions in Alzheimer's Disease

Pierre‐André Lafon, Mireille Elodie Tsitokana, Yen-Ling Lian, Laurent Prézeau et al.
Advanced Science
Alzheimer's disease research and treatments
article

Divergent Roles of mGlu2 and mGlu3 Receptors in Amyloid‐β Production and Cognitive Dysfunctions in Alzheimer's Disease

Pierre‐André Lafon, Mireille Elodie Tsitokana, Yen-Ling Lian, Laurent Prézeau, Véronique Perrier, Clementine Philibert, Jean‐Philippe Pin, Patrick Chames, Julie Kniazeff, Philippe Rondard, Salomé Roux, Marta Cimadevila, Séverine Diem, Anaïs Menny, Franck Vandermoere, Mathieu Oosterlaken, Jessica Monnic, Julie Bessié, Jianfeng Liu, Sylvie Claeysen, Gaëlle Dudon, Ugo Guy Alenda
article en

Abstract

Immunotherapy is a promising avenue for reducing amyloid-β (Aβ) accumulation, a hallmark of Alzheimer's disease (AD) pathology. Camelid single domain antibodies, called nanobodies, offer several advantages over conventional monoclonal antibodies, including improved brain penetration and fine-tuning of the targeted neuroreceptors, and may represent an effective strategy to modulate Aβ production. Among potential therapeutic targets, group II metabotropic glutamate receptors (mGluR2 and mGluR3) have been implicated in Aβ regulation, though their individual contributions remain unclear. Here, we showed that activation of mGluR2 significantly increases Aβ peptides and sAPPβ production in a cellular model, by enhancing the internalization of amyloid precursor protein (APP) and its subsequent amyloidogenic processing. In contrast, mGluR3 directly interacts with APP, protecting it from amyloidogenic cleavage and favoring its non-amyloidogenic processing. We used a brain-penetrant nanobody acting as a selective positive allosteric modulator of mGluR2 to validate its role in Aβ dynamics in vivo. Chronic administration of this nanobody in 5xFAD mice accelerated amyloid plaque deposition and worsened cognitive deficits. These findings establish mGluR2 as a target in AD and demonstrate that its selective modulation by nanobodies influences Aβ pathology. This also highlights the potential of nanobodies as next-generation therapeutic agents for modulating neuroreceptors activity in AD.

Advanced Science
Centre National de la Recherche Scientifique (FR), Inserm (FR), Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN), Institute for Neurosciences of Montpellier (FR), Centre de Recherche en Cancérologie de Marseille (FR), Institut Paoli-Calmettes (FR), Institut de Génomique Fonctionnelle (FR), Huazhong University of Science and Technology (CN)
Agence Nationale de la Recherche, National Natural Science Foundation of China, Fondation pour la Recherche Médicale, European Research Council, National Key Research and Development Program of China
Openalex Percentile: Top 23%
Alzheimer's disease research and treatments
DOIOpen Access PDFOpenAlex
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