Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: Pregabalin may have an effect on Aβ that merits further investigation, but our study does not suggest that pregabalin contributes substantially to amyloid pathology.

背景：已提出钙失调在阿尔茨海默病病理学的发展中起致病作用。普瑞巴林是一种已获准供人使用的化合物，以处方药 Lyrica 的形式上市销售。它结合 P/Q 型电压门控钙通道的 α2-δ 亚基，降低钙内流，为癫痫和神经性疼痛提供有效的治疗。

目的：我们假设在淀粉样斑块附近的神经元过程中增加的静息钙在神经炎性营养不良的发展和淀粉样蛋白病理学的进一步进展中起作用。

方法：5XFAD 小鼠口服普瑞巴林 12 周，然后使用免疫印迹和免疫荧光成像来量化普瑞巴林与安慰剂治疗小鼠相比的神经炎营养不良和淀粉样蛋白沉积。

结果：治疗并未减少神经炎性营养不良或淀粉样蛋白沉积的标志物。在逐个斑块的基础上对神经炎性营养不良的图像分析显示，在普瑞巴林处理的小鼠皮层面积为 50-450 μm2 的斑块中，LAMP1 与 Aβ42 的相对比例略有增加，但并不显着。此外，测得的普瑞巴林脑浓度与皮质中BACE1和Aβ的相对水平之间存在统计学上显着的正相关。在海马体中没有观察到这种关系，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较大程度的神经炎性营养不良有关。

结论：普瑞巴林可能对 Aβ 有影响，值得进一步研究，但我们的研究并未表明普瑞巴林对淀粉样蛋白病理学有重大贡献。