Govindarajulu Manoj, Pinky Priyanka D, Steinke Ian, Bloemer Jenna, Ramesh Sindhu, Kariharan Thiruchelvan, Rella Robert T, Bhattacharya Subhrajit, Dhanasekaran Muralikrishnan, Suppiramaniam Vishnu, Amin Rajesh H
Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States.
Center for Neuroscience, Auburn University, Auburn, AL, United States.
Front Mol Neurosci. 2020 Aug 12;13:138. doi: 10.3389/fnmol.2020.00138. eCollection 2020.
Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer's model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention.
肠道微生物群失调与包括糖尿病、肥胖症和心血管疾病在内的代谢性疾病密切相关。最近的研究表明，三甲胺 N-氧化物（TMAO）这种肠道微生物依赖性代谢产物与年龄相关的认知衰退的发展有关。然而，TMAO 对神经元功能影响的机制尚未阐明。在本研究中，我们通过测量 TMAO 的血浆和脑内水平，研究了 TMAO 与阿尔茨海默病模型（3×Tg-AD）和胰岛素抵抗（瘦素缺乏的 db/db）小鼠突触可塑性缺陷之间的关系。我们观察到，与野生型小鼠相比，db/db 和 3×Tg-AD 小鼠的血浆和脑内 TMAO 水平均升高。此外，随着小鼠年龄增长，TMAO 水平进一步升高。与野生型小鼠相比，两组小鼠均出现以长时程增强（LTP）降低形式的突触可塑性缺陷。为了进一步探究 TMAO 对神经元功能的影响，我们通过用 TMAO 孵育野生型海马脑片建立了一个模型，发现突触传递受损。我们观察到，TMAO 在 TMAO 处理的脑片中以及在 db/db 和 3×Tg-AD 小鼠中均诱导了 PERK-EIF2α-内质网应激信号轴。最后，我们还观察到突触前改变和突触后受体表达减少。我们的研究结果表明，TMAO 可能通过内质网应激介导的 PERK 信号通路诱导突触可塑性缺陷。我们的结果为 TMAO 可能通过促进内质网应激诱导认知缺陷的机制提供了新的见解，并确定了潜在的治疗干预靶点。
