Chronic potentiation of metabotropic glutamate receptor 2 with a nanobody accelerates amyloidogenesis in Alzheimer’s disease

Abstract Immunotherapy of Alzheimer’s disease (AD) is a promising approach to reduce the accumulation of amyloid-beta (Aβ), a critical event in the onset of the disease. Targeting the group II metabotropic glutamate receptors, mGlu2 and mGlu3, could be important in controlling Aβ production, although their respective contribution remains unclear due to the lack of selective tools. Here, we show that enhancing mGlu2 receptor activity increases Aβ1-42 peptide production whereas activation of mGlu3 has no effect. We show that such a difference likely results from the direct interaction of APP with mGlu3, but not with mGlu2 receptors, that prevents APP amyloidogenic cleavage and Aβ1-42 peptides production. We then show that chronic treatments of the AD model 5xFAD mice with a brain-penetrating mGlu2-potentiating nanobody accelerated amyloid aggregation and exacerbated memory deficits, but had no effect in control mice. Our results confirm that a selective mGluR2 activation exacerbates AD disease development, suggesting that therapeutic benefices could be obtained with blockers of this receptor. Our study also provides the proof-of-concept that chronic administration of nanobodies targeting neuroreceptors can be envisioned to treat brain diseases. Competing Interest Statement P.R. and J.-P.P. are involved in a collaborative team between the CNRS and Revvity Cisbio. The remaining authors declare no competing interests.