Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
Biomolecules. 2023 Sep 27;13(10):1461. doi: 10.3390/biom13101461.
Alzheimer's disease (AD), a devastating neurodegenerative disease characterized by cognitive dysfunctions, is associated with high levels of amyloid beta 42 (Aβ), which is believed to play a role in cellular damage and signaling changes in AD. Decanoic acid has been shown to be therapeutic in AD. Glutamatergic signaling within neurons and astrocytes of the CA1 region of the hippocampus is critical in cognitive processes, and previous work has indicated deficiencies in this signaling in a mouse model of AD. In this study, we investigated glutamate-mediated signaling by evaluating AMPA-mediated calcium rises in female and male CA1 neurons and astrocytes in a mouse model of AD and examined the potential of decanoic acid to normalize this signaling. In brain slices from 5xFAD mice in which there are five mutations leading to increasing levels of Aβ, AMPA-mediated calcium transients in CA1 neurons and astrocytes were significantly lower than that seen in wildtype controls in both females and males. Interestingly, incubation of 5xFAD slices in decanoic acid restored AMPA-mediated calcium levels in neurons and astrocytes in both females and males to levels indistinguishable from those seen in wildtype, whereas similar exposure to decanoic acid did not result in changes in AMPA-mediated transients in neurons or astrocytes in either sex in the wildtype. Our data indicate that one mechanism by which decanoic acid could improve cognitive functioning is through normalizing AMPA-mediated signaling in CA1 hippocampal cells.
阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，其特征是认知功能障碍，与高水平的淀粉样β 42（Aβ）有关，据信 Aβ 在 AD 中的细胞损伤和信号变化中起作用。已证明癸酸在 AD 中有治疗作用。海马 CA1 区神经元和星形胶质细胞中的谷氨酸能信号对于认知过程至关重要，先前的工作表明 AD 小鼠模型中存在这种信号的缺陷。在这项研究中，我们通过评估 AD 小鼠模型中 CA1 神经元和星形胶质细胞中 AMPA 介导的钙升高，研究了谷氨酸介导的信号，检查了癸酸使这种信号正常化的潜力。在具有导致 Aβ 水平升高的五个突变的 5xFAD 小鼠的脑片中，CA1 神经元和星形胶质细胞中的 AMPA 介导的钙瞬变明显低于野生型对照的雌性和雄性。有趣的是，在癸酸孵育下，5xFAD 切片中的神经元和星形胶质细胞中的 AMPA 介导的钙水平在雌性和雄性中均恢复到与野生型相似的水平，而在野生型中，类似的癸酸暴露不会导致神经元或星形胶质细胞中 AMPA 介导的瞬变发生变化。我们的数据表明，癸酸改善认知功能的一种机制是通过使 CA1 海马细胞中的 AMPA 介导的信号正常化。
