Chronic Pharmacological mGluR5 Inhibition Prevents Cognitive Impairment and Reduces Pathogenesis in an Alzheimer Disease Mouse Model

Area of Science:

• Neuroscience
• Pharmacology
• Alzheimer Disease Research

Background:

• Beta-amyloid (Aβ) oligomers are key contributors to Alzheimer disease (AD) pathophysiology.
• Metabotropic glutamate receptor 5 (mGluR5) acts as a receptor for Aβ oligomers and cellular prion proteins.
• Genetic deletion of mGluR5 in AD mouse models improves cognition and reduces Aβ pathology.

Purpose of the Study:

• To investigate the therapeutic potential of mGluR5-selective negative allosteric modulators in AD mouse models.
• To evaluate the effects of CTEP on cognitive function, Aβ plaque deposition, and soluble Aβ oligomer concentrations.

Main Methods:

• Chronic administration of CTEP, an orally bioavailable mGluR5 negative allosteric modulator, to APPswe/PS1ΔE9 and 3xTg-AD male mice.
• Assessment of cognitive function using behavioral tests.
• Quantification of Aβ plaque deposition and soluble Aβ oligomer concentrations.

Main Results:

• CTEP administration reversed cognitive decline in APPswe/PS1ΔE9 mice.
• CTEP treatment reduced Aβ plaque deposition and soluble Aβ oligomer concentrations in both APPswe/PS1ΔE9 and 3xTg-AD male mice.
• CTEP demonstrated similar structure, potency, and selectivity to Basimglurant.

Conclusions:

• mGluR5 negative allosteric modulators, such as CTEP, show promise as a therapeutic strategy for Alzheimer disease.
• CTEP or its analogue Basimglutant may be effective treatments for AD patients.