A M1 muscarinic acetylcholine receptor-specific positive allosteric modulator VU0486846 reduces neurogliosis in female Alzheimer’s mice - 22/03/24
Abstract |
Alzheimer's disease (AD) is the most prevalent type of dementia, disproportionately affecting females, who make up nearly 60% of diagnosed cases. In AD patients, the accumulation of beta-amyloid (Aβ) in the brain triggers a neuroinflammatory response driven by neuroglia, worsening the condition. We have previously demonstrated that VU0486846, an orally available positive allosteric modulator (PAM) targeting M1 muscarinic acetylcholine receptors, enhances cognitive function and reduces Aβ pathology in female APPswe/PSEN1ΔE9 (APP/PS1) mice. However, it remained unclear whether these improvements were linked to a decrease in neuroglial activation. To investigate, we treated nine-month-old APP/PS1 and wildtype mice with VU0486846 for 8 weeks and analyzed brain slices for markers of microglial activation (ionized calcium binding adaptor molecule 1, Iba1) and astrocyte activation (Glial fibrillary acidic protein, GFAP). We find that VU0486846 reduces the presence of Iba1-positive microglia and GFAP-positive astrocytes in the hippocampus of female APP/PS1 mice and limits the recruitment of these cells to remaining Aβ plaques. This study sheds light on an additional mechanism through which novel M1 mAChR PAMs exhibit disease-modifying effects by reducing neuroglial activation and underscore the potential of these ligands for the treatment of AD, especially in females.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Activation of M1 mAChR with VU0486846 reduces Aβ plaques in female APP/PS1 mice. |
• | VU0486846 reduces microgliosis around Aβ plaques in the hippocampus of APP/PS1 mice. |
• | VU0486846 decreases astrocyte reactivity around hippocampal plaques in APP/PS1 mice. |
Abbreviations : AD, APP, APP/PS1, Aβ, BACE1, Iba1, GPCR, GFAP, M1 mAChR, PAM, VU0486846
Keywords : GPCR, muscarinic, acetylcholine, memory, Beta amyloid, neuroglia
Plan
Vol 173
Article 116388- avril 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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