mGluR5 nanobodies as innovative therapeutic tools for Alzheimer’s disease – NanoThALZ

Metabotropic glutamate receptor 5 (mGluR5) is highly expressed in brain regions responsible for memory and learning. Aberrant mGluR5 signaling and associated synaptic failure are now considered as an emerging pathophysiological mechanism of Alzheimer’s disease (AD). Therefore, mGluR5 represents an attractive therapeutic target for AD since it plays a central role in regulating both Abeta42 and Tau pathology signaling, the two main markers of AD. Allosteric modulators (AMs) of mGluR5 are divided into positive allosteric modulators (PAMs), negative (NAMs) and silent (SAMs). Interestingly, mGluR5 NAM, CTEP, has proven to be the most effective mGluR5 ligand in improving memory function and ameliorating Abeta42 pathology in AD mouse models.
We recently developed innovative biological tools, mGluR1 and mGluR5 camelid nanobodies, with high affinity and selectivity, and various allosteric properties (PAM, NAM, SAM). Our objectives are to evaluate these nanobodies as potential pharmacological agents for AD. First, we will use them as tools to set-up nanobody-based time-resolved FRET biosensors to quantify the endogenous mGluR1 and mGluR5 and to measure their pharmacological activity. These nanobodies will be helpful to identify and characterize the heterodimers mGluR1-R5 as potential new targets in AD. Second, we will evaluate the pharmacological potential of these mGlu nanobodies, used alone or in combination on differentiated inducible pluripotent stem cells (iPSCs) derived from AD patients. And third, we will evaluate in vivo these nanobodies, as innovative therapeutic tools in two transgenic mice models of AD, based on the expertise of Partner #1 in targeting nanobodies to the brain after peripheral injection. Impact on Abeta and Tau markers will be measured, as well as their behavioral effects to determine if nanobodies can rescue memory deficits. This work will shed light on the use of mGlu nanobodies as possible pharmacological tools for the treatment of AD.