O-demethyl galantamine alters protein expression in cerebellum of 5xFAD mice

İrem Kiriş; Merve Karayel Başar; Büşra Gürel; Tomasz Mroczek; Ahmet Tarık Baykal

doi:10.55730/1300-0152.2692

O-demethyl galantamine alters protein expression in cerebellum of 5xFAD mice

Turk J Biol. 2024 May 28;48(3):163-173. doi: 10.55730/1300-0152.2692. eCollection 2024.

Authors

İrem Kiriş^{1

2}, Merve Karayel Başar¹, Büşra Gürel³, Tomasz Mroczek⁴, Ahmet Tarık Baykal⁵

Affiliations

¹ Department of Biochemistry and Molecular Biology, Institute of Health Sciences, Acıbadem Mehmet Ali Aydınlar University, İstanbul, Turkiye.
² Faculty of Engineering and Natural Sciences, Sabancı University, İstanbul, Turkiye.
³ Nanotechnology Research and Application Center, SUNUM, Sabancı University, İstanbul, Turkiye.
⁴ Chair and Department of Pharmacognosy, Medical University of Lublin, Lublin, Poland.
⁵ Department of Medical Biochemistry, Faculty of Medicine, Acıbadem Mehmet Ali Aydınlar University, İstanbul, Turkiye.

Abstract

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 at the molecular level in a 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 cortex, hippocampus, and cerebellum regions of the brain. 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. Reregulation 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.

Keywords: 5xFAD; Alzheimer’s disease; label-free proteomics; neurodegeneration; o-demethyl galantamine; sanguinine.

Grants and funding

This study was financially supported by The Scientific and Technological Research Council of Türkiye (TÜBİTAK) – National Centre for Research and Development of Poland (NCBR) Bilateral Cooperation program under project numbers 215S168 and 4/POLTUR-1/2016.