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

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.