Neuroprotective role of alendronate against APP processing and neuroinflammation in mice fed a high fat diet.,Brain Research Bulletin

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Neuroprotective role of alendronate against APP processing and neuroinflammation in mice fed a high fat diet.
Brain Research Bulletin ( IF 3.5 ) Pub Date : 2020-05-07 , DOI: 10.1016/j.brainresbull.2020.04.010
Saima Zameer ₁ , Mahtab Alam ₁ , Salman Hussain ₁ , Divya Vohora ₂ , Javed Ali ₃ , Abul Kalam Najmi ₂ , Mohd Akhtar ₂

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Obesity and consumption of diet rich in fat are known to contribute to the development of Alzheimer's disease (AD) which is a complex and multifactorial neurodegenerative disease and a leading cause of mortality with unmet medical needs. Hypercholesterolemia was discovered to increase neuropathological changes alongwith cognitive decline in AD mouse models but still the underlying mechanism is elusive. Furthermore, isoprenoids, the crucial products of Mevalonate-pathway produced by the action of farnesyl pyrophosphate synthase (FPPS) enzyme, are also demonstrated to play a key role in AD. Nevertheless, bisphosphonates target this enzyme in order to treat osteoporosis and also found to alleviate dementia in such patients. As per the cited inhibitory action of alendronate, against acetylcholinesterase and cholesterol level, we hypothesized to explore the potential of alendronate against high fat diet (HFD) induced neuropathologies and cognitive disabilities in AD mouse model. Here we noticed that in mice provided with HFD for 14 weeks, spatial memory was compromised as interpreted in different behavioral paradigms. Together with cognitive depletion, there was observed a provoking effect on amyloid precursor protein (APP)-processing via amyloidogenic pathway due to enhancedβ-site APP cleaving enzyme-1(BACE-1) level which in turn leads to augmented release of amyloid beta(Aβ) in hippocampus of HFD mice. Relevant to these, significant elevation in hippocampal level of neuroinflammatory cytokines, oxidative stress markers and isoprenoids and serum cholesterol were also found after HFD exposure. Marked reversal of cognitive impairment, enhanced APP-processing, neuroinflammation along with other neuropathological alterations in hippocampus was demonstrated following oral administration of alendronate (1.76 mg/kg) for 15 days despite of HFD treatment. These changes were noted to be due to modulation of isoprenoids and cholesterol level by alendronate. Supporting these, histopathological analysis done by congo red revealed the reduced Aβ deposition in hippocampus of drug treated HFD mice The current outcomes provide important implications for the contribution of Mevalonate-pathway and HFD for the onset of AD and also support alendronate as a prominent intervention for amelioration of AD-like pathologies.

中文翻译：

阿仑膦酸钠对高脂肪饮食小鼠的 APP 加工和神经炎症的神经保护作用。

众所周知，肥胖和食用富含脂肪的饮食会导致阿尔茨海默病 (AD) 的发展，阿尔茨海默病 (AD) 是一种复杂的多因素神经退行性疾病，是医疗需求未得到满足的主要死亡原因。发现高胆固醇血症会增加 AD 小鼠模型的神经病理变化以及认知能力下降，但其潜在机制仍然难以捉摸。此外，类异戊二烯是由法呢基焦磷酸合酶 (FPPS) 酶作用产生的甲羟戊酸途径的关键产物，也被证明在 AD 中起关键作用。尽管如此，双膦酸盐靶向这种酶以治疗骨质疏松症，并且还发现可以缓解此类患者的痴呆症。根据引用的阿仑膦酸盐抑制乙酰胆碱酯酶和胆固醇水平的作用，我们假设探索阿仑膦酸钠对 AD 小鼠模型中高脂肪饮食 (HFD) 诱导的神经病理学和认知障碍的潜力。在这里，我们注意到，在使用 HFD 14 周的小鼠中，空间记忆受到损害，正如在不同行为范式中所解释的那样。与认知耗竭一起，由于β位点APP裂解酶1（BACE-1）水平增强，β位点APP裂解酶1（BACE-1）水平增强，进而导致β淀粉样蛋白的释放增加，因此观察到对淀粉样前体蛋白（APP）通过淀粉样蛋白途径加工产生刺激作用。 Aβ) 在 HFD 小鼠的海马中。与这些相关的是，在 HFD 暴露后还发现海马神经炎细胞因子、氧化应激标志物和类异戊二烯和血清胆固醇水平显着升高。显着逆转认知障碍，增强应用程序处理，尽管进行了 HFD 治疗，但在口服阿仑膦酸钠 (1.76 mg/kg) 15 天后，神经炎症以及海马的其他神经病理学改变得到证实。注意到这些变化是由于阿仑膦酸钠对类异戊二烯和胆固醇水平的调节。支持这些，刚果红进行的组织病理学分析显示药物治疗的 HFD 小鼠海马中 Aβ 沉积减少。改善 AD 样病理。注意到这些变化是由于阿仑膦酸钠对类异戊二烯和胆固醇水平的调节。支持这些，刚果红进行的组织病理学分析显示药物治疗的 HFD 小鼠海马中 Aβ 沉积减少。改善 AD 样病理。注意到这些变化是由于阿仑膦酸钠对类异戊二烯和胆固醇水平的调节。支持这些，刚果红进行的组织病理学分析显示药物治疗的 HFD 小鼠海马中 Aβ 沉积减少。改善 AD 样病理。

更新日期：2020-05-08

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