O-Demethyl Galantamine Alters Protein Expression In Cerebellum Of 5Xfad Mice

<strong>Background/aim:</strong> 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). 

<strong>Materials and methods:</strong> 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. 

<strong>Results:</strong> 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.

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

<strong>背景/目的：</strong>阿尔茨海默病（Alzheimer’s disease, AD）是最常见的健康问题之一，其特征为记忆丧失、严重行为障碍，最终导致死亡。尽管已有大量研究，目前仍无能够治疗AD或阻止其进展的药物。既往体外试验（in vitro tests）表明，去甲基加兰他敏（O-demethyl galantamine, ODG）因其乙酰胆碱酯酶抑制活性比加兰他敏（galantamine, GAL）高10倍，故可能具有治疗潜力。

<strong>材料与方法：</strong>我们旨在从分子层面评估ODG对12月龄5xFAD阿尔茨海默病小鼠模型（5xFAD Alzheimer’s mouse model）的影响。为此，在给予ODG和作为阳性对照的GAL后，研究了大脑皮层（cortex）、海马体（hippocampus）和小脑（cerebellum）区域的蛋白质变化。令人意外的是，GAL在皮层显著改变蛋白质，而ODG仅在小脑发挥作用。

<strong>结果：</strong>GNB1、GNB2、NDUFS6、PAK2和RhoA蛋白被确定为ODG处理小鼠小脑内的前5个核心蛋白。通过Ras信号通路（Ras signaling）和逆行内源性大麻素信号通路（retrograde endocannabinoid signaling pathway）对这些蛋白的再调节（这些通路被发现存在富集），可能有助于逆转AD诱导的分子改变。

<strong>结论：</strong>我们认为，由于ODG特异性靶向小脑，其可进一步被评估用于阿尔茨海默病的联合治疗。