Biology subjects

Desrumaux, C.

Publications and source records attributed to Desrumaux, C..

2 recordsLinked to original sources

bioRxiv2025

Shedding light on left hippocampal mGlu5 in Alzheimer's disease

Metabotropic glutamate receptor 5 (mGlu5) plays a central role in synaptic plasticity and memory, and has emerged as a potential therapeutic target in Alzheimers disease (AD). While asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show the presence of a physiological left-right asymmetry in mGlu5 expression in the hippocampus of wild-type mice, with higher levels in the left hemisphere, consistent with previous observations. Importantly, we reveal that this asymmetry is lost in J20 AD model mice due to a selective reduction of mGlu5 in the left hippocampus. Then, using the light-controllable negative allosteric modulator Alloswitch-1, we demonstrate that selective inhibition of mGlu5 in the left, but not right, hippocampus is both necessary and sufficient to restore working and short-term memory in J20 mice. This left-specific modulation also reverses downstream pathological signaling, including aberrant Pyk2 and GSK3-{beta} activation and tau hyperphosphorylation, in both hippocampi. Our findings identify a functional lateralization of mGlu5 in hippocampal circuits and highlight the potential of spatially targeted photopharmacology for precise intervention in early AD pathology.

neuroscience↗

bioRxiv2022

Microglial P2X4 receptors promote ApoE degradation and cognitive deficits in Alzheimer disease

Numerous evidence support that microglia contributes to the progression of Alzheimers disease. P2X4 receptors are ATP-gated channels, which are de novo expressed in a subset of reactive microglia associated to various pathological contexts, contributing to microglial functions. Here, we investigated the role of P2X4 in the context of Alzheimer disease (AD). In both human AD brain and APPswe/PSEN1dE9 mice, P2X4 is almost exclusively expressed in plaque associated microglia. Genetic deletion of P2rx4 results in the reversal of cognitive declines and in a lower amount of soluble A{beta}1 -42 in 12 months old APP/PS1 mice, while no obvious alteration of plaque associated microglia characteristics is observed. Using proteomic, we identified ApoE as a specific P2X4 interacting protein. We found that P2X4 regulates lysosomal cathepsin B activity promoting ApoE degradation; P2rx4 deletion results in higher amount of intracellular and secreted ApoE in both BMDM and microglia from APP/PS1 brain. Our results support that microglial P2X4 promotes lysosomal ApoE degradation, indirectly altering A{beta} peptide clearance, which in turn might promote synaptic dysfunctions and cognitive deficits. Our findings also uncover a specific interplay between purinergic signaling, microglial ApoE, sA{beta} species and cognitive deficits associated with AD.

neuroscience↗