Noncanonical Metabotropic Glutamate Receptor 5 Signaling in Alzheimer's Disease

Metabotropic glutamate receptor 5 (mGluR5) is ubiquitously expressed in brain regions responsible for memory and learning. It plays a key role in modulating rapid changes in synaptic transmission and plasticity. mGluR5 supports long-term changes in synaptic strength by regulating the transcription and translation of essential synaptic proteins. beta-Amyloid 42 (A beta 42) oligomers interact with a mGluR5/cellular prion protein (PrPC) complex to disrupt physiological mGluR5 signal transduction. Aberrant mGluR5 signaling and associated synaptic failure are considered an emerging pathophysiological mechanism of Alzheimer's disease (AD). Therefore, mGluR5 represents an attractive therapeutic target for AD, and recent studies continue to validate the efficacy of various mGluR5 allosteric modulators in improving memory deficits and mitigating disease pathology. However, sexspecific differences in the pharmacology of mGluR5 and activation of noncanonical signaling downstream of the receptor suggest that its utility as a therapeutic target in female AD patients needs to be reconsidered.

Automated summary

mGluR5 is widely expressed in the brain and plays a key role in memory and learning, synaptic transmission, and plasticity. Its dysfunction, specifically in response to Aβ42 oligomers, is believed to contribute to the pathophysiology of AD. As a potential therapeutic target for AD, recent studies have demonstrated the efficacy of mGluR5 allosteric modulators in improving memory deficits and mitigating disease pathology. However, the pharmacological differences and downstream signaling activation of mGluR5 in different genders suggest the need for reevaluation of its therapeutic potential in female AD patients.