Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States.
Department of Chemistry, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60611, United States.
Curr Alzheimer Res. 2021;18(4):283-297. doi: 10.2174/1567205018666210713125333.
Calcium dysregulation has been proposed to play a causative role in the development of Alzheimer's disease pathology. Pregabalin is a compound already approved for human use, marketed as the prescription drug Lyrica. It binds the α2-δ subunit of P/Q-type voltagegated calcium channels, lowering calcium influx and providing effective treatment for epilepsy and neuropathic pain.
We hypothesize that increased resting calcium in neuronal processes near amyloid plaques plays a role in the development of neuritic dystrophies and further progression of amyloid pathology.
5XFAD mice were treated orally for 12 weeks with pregabalin, then immunoblotting and immunofluorescent imaging were used to quantify neuritic dystrophy and amyloid deposition in pregabalin compared to placebo-treated mice.
The treatment did not decrease markers of neuritic dystrophy or amyloid deposition. The image analysis of neuritic dystrophy on a plaque-by-plaque basis showed a small non-significant increase in the relative proportion of LAMP1 to Aβ42 in plaques with areas of 50-450 μm2 in the cortex of pregabalin-treated mice. In addition, there was a statistically significant positive correlation between the measured cerebral concentration of pregabalin and the relative levels of BACE1 and Aβ in the cortex. This relationship was not observed in the hippocampus, and there was no increase in average Aβ levels in pregabalin treated mice compared to placebo. We confirmed previous findings that smaller amyloid plaques are associated with a greater degree of neuritic dystrophy.
Pregabalin may have an effect on Aβ that merits further investigation, but our study does not suggest that pregabalin contributes substantially to amyloid pathology.
钙稳态失调被认为在阿尔茨海默病病理的发展中起因果作用。普瑞巴林是一种已被批准用于人类的化合物，以处方药力如太上市。它与 P/Q 型电压门控钙通道的 α2-δ 亚基结合，降低钙内流，为癫痫和神经性疼痛提供有效治疗。
我们假设淀粉样斑块附近神经元突起中的静息钙增加在神经突营养不良的发展和淀粉样蛋白病理的进一步进展中起作用。
5XFAD 小鼠用普瑞巴林口服治疗 12 周，然后用免疫印迹和免疫荧光成像来定量普瑞巴林与安慰剂治疗的小鼠相比，神经突营养不良和淀粉样蛋白沉积。
该治疗并未降低神经突营养不良或淀粉样蛋白沉积的标志物。基于斑块的神经突营养不良的图像分析显示，在皮质中面积为 50-450μm2 的斑块中，普瑞巴林治疗小鼠的 LAMP1 与 Aβ42 的相对比例有小但无统计学意义的增加。此外，在大脑中普瑞巴林的测量浓度与皮质中的 BACE1 和 Aβ 的相对水平之间存在统计学上显著的正相关。这种相关性在海马体中没有观察到，而且与安慰剂相比，普瑞巴林治疗的小鼠的平均 Aβ 水平没有增加。我们证实了先前的发现，即较小的淀粉样斑块与更严重的神经突营养不良相关。
普瑞巴林可能对 Aβ 有影响，值得进一步研究，但我们的研究并不表明普瑞巴林对淀粉样蛋白病理有实质性贡献。
