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O-demethyl Galantamine Alters Protein Expression in Cerebellum of 5xFAD Mice

2024    Kiris, İrem; Karayel-Basar, Merve; Gurel, Busra; Mroczek, Tomasz; Baykal, Ahmet Tarik

Background/aim: Alzheimer’s disease (AD), one of the most common health issues, is characterized by memory loss, severe behavioral disorders, and eventually death. Despite many studies, there are still no drugs that can treat AD or stop it from progressing. Previous in vitro tests showed that O-demethyl galantamine (ODG) might have therapeutic potential owing to its 10 times higher acetylcholinesterase inhibitory activity than galantamine (GAL). 

Materials and methods: We aimed to assess the effect of ODG on a molecular level 12-month-old 5xFAD Alzheimer’s mouse model. To this end, following the administrations of ODG and GAL, used as a positive control, protein alterations were investigated in the brain’s cortex, hippocampus, and cerebellum regions. Surprisingly, GAL altered proteins prominently in the cortex, while ODG exclusively exerted its effect on the cerebellum. 

Results: GNB1, GNB2, NDUFS6, PAK2, and RhoA proteins were identified as the top 5 hub proteins in the cerebellum of ODG treated mice. Re-regulation of these proteins through Ras signaling and retrograde endocannabinoid signaling pathways, which were found to be enriched, might contribute to reversing AD-induced molecular changes.

Conclusion: We suggest that, since it targets specifically the cerebellum, ODG may be further evaluated for combination therapies for AD.