Department of Health Science and Technology, Gachon Advanced Institute for Health Sciences & Technology, Gachon University, Incheon 21999, Republic of Korea.
Department of Pharmacology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea.
Int J Mol Sci. 2023 Aug 21;24(16):13010. doi: 10.3390/ijms241613010.
Alzheimer's disease (AD) is one representative dementia characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain, resulting in cognitive decline and memory loss. AD is associated with neuropsychiatric symptoms, including major depressive disorder (MDD). Recent studies showed a reduction in mGluR5 expression in the brains of stress-induced mice models and individuals with MDD compared to controls. In our study, we identified depressive-like behavior and memory impairment in a mouse model of AD, specifically in the 6xTg model with tau and Aβ pathologies. In addition, we investigated the expression of mGluR5 in the brains of 6xTg mice using micro-positron emission tomography (micro-PET) imaging, histological analysis, and Western blot analysis, and we observed a decrease in mGluR5 levels in the brains of 6xTg mice compared to wild-type (WT) mice. Additionally, we identified alterations in the ERK/AKT/GSK-3β signaling pathway in the brains of 6xTg mice. Notably, we identified a significant negative correlation between depressive-like behavior and the protein level of mGluR5 in 6xTg mice. Additionally, we also found a significant positive correlation between depressive-like behavior and AD pathologies, including phosphorylated tau and Aβ. These findings suggested that abnormal mGluR5 expression and AD-related pathologies were involved in depressive-like behavior in the 6xTg mouse model. Further research is warranted to elucidate the underlying mechanisms and explore potential therapeutic targets in the intersection of AD and depressive-like symptoms.
阿尔茨海默病（AD）是一种代表性的痴呆症，其特征是大脑中淀粉样β（Aβ）斑块和神经原纤维缠结（NFT）的积累，导致认知能力下降和记忆力丧失。AD 与神经精神症状有关，包括重度抑郁症（MDD）。最近的研究表明，与对照组相比，应激诱导的小鼠模型和 MDD 个体大脑中的 mGluR5 表达减少。在我们的研究中，我们在 AD 小鼠模型中发现了抑郁样行为和记忆障碍，特别是在具有 tau 和 Aβ病理的 6xTg 模型中。此外，我们使用微正电子发射断层扫描（micro-PET）成像、组织学分析和 Western blot 分析研究了 6xTg 小鼠大脑中的 mGluR5 表达，观察到 6xTg 小鼠大脑中的 mGluR5 水平与野生型（WT）小鼠相比降低。此外，我们还发现 6xTg 小鼠大脑中的 ERK/AKT/GSK-3β信号通路发生改变。值得注意的是，我们发现 6xTg 小鼠中抑郁样行为与 mGluR5 蛋白水平之间存在显著负相关。此外，我们还发现抑郁样行为与 AD 病理之间存在显著正相关，包括磷酸化 tau 和 Aβ。这些发现表明，6xTg 小鼠模型中异常的 mGluR5 表达和 AD 相关病理与抑郁样行为有关。需要进一步研究阐明潜在机制，并探索 AD 和抑郁样症状交叉点的潜在治疗靶点。
