Abstract：
While symptoms related to lower urinary tract dysfunction (LUTD) are common in individuals with Alzheimer\'s disease (AD), pathophysiological links between AD and LUTD remain unclear.
This study aimed to investigate whether AD neuropathology would cause autonomic dysfunction along the spinal cord-bladder axis, which could result in alterations in bladder muscle kinetics.
We utilized APPNL-G-F/NL-G-F knock-in (APP KI) and APPwt/wt (wild-type) mice at two different ages, 4- and 10-month-old, to investigate how AD impacts bladder tissue function by immunohistochemistry, western blotting, and pharmacomyography.
We showed that the mucosal layer partially separated from the detrusor in 10-month-old APP KI mouse bladders. Although there was no detectable amyloid deposition in the APP KI bladder, we found amyloid plaques in APP KI lumbar spinal cord. Further immunoblot analysis revealed that tyrosine hydroxylase protein levels were significantly reduced in both 4- and 10-month-old bladder tissues, suggesting reduction of norepinephrine synthesis in APP KI mouse bladders. In contrast, the level of β2 adrenergic receptor was increased in 4-month-old but not 10-month-old APP KI bladders. In bladder strips, the adrenergic agonist isoproterenol induced increased relaxation in 4- but not 10-month-old APP KI bladders. With 10 Hz electrical field stimulation, 10-month-old APP KI bladder strips were more responsive than wild-type controls, with no differences observed in 4-month-old APP KI bladders.
APP KI mice exhibit LUTD, which is likely arising from amyloid pathology in the spinal cord, and results in maturational declines in presynaptic activity combined with compensatory postsynaptic upregulation.
This study aimed to investigate whether AD neuropathology would cause autonomic dysfunction along the spinal cord-bladder axis, which could result in alterations in bladder muscle kinetics.
We utilized APPNL-G-F/NL-G-F knock-in (APP KI) and APPwt/wt (wild-type) mice at two different ages, 4- and 10-month-old, to investigate how AD impacts bladder tissue function by immunohistochemistry, western blotting, and pharmacomyography.
We showed that the mucosal layer partially separated from the detrusor in 10-month-old APP KI mouse bladders. Although there was no detectable amyloid deposition in the APP KI bladder, we found amyloid plaques in APP KI lumbar spinal cord. Further immunoblot analysis revealed that tyrosine hydroxylase protein levels were significantly reduced in both 4- and 10-month-old bladder tissues, suggesting reduction of norepinephrine synthesis in APP KI mouse bladders. In contrast, the level of β2 adrenergic receptor was increased in 4-month-old but not 10-month-old APP KI bladders. In bladder strips, the adrenergic agonist isoproterenol induced increased relaxation in 4- but not 10-month-old APP KI bladders. With 10 Hz electrical field stimulation, 10-month-old APP KI bladder strips were more responsive than wild-type controls, with no differences observed in 4-month-old APP KI bladders.
APP KI mice exhibit LUTD, which is likely arising from amyloid pathology in the spinal cord, and results in maturational declines in presynaptic activity combined with compensatory postsynaptic upregulation.
摘要：
背景：虽然与下尿路功能障碍（LUTD）相关的症状在阿尔茨海默病（AD）患者中很常见，AD和LUTD之间的病理生理联系尚不清楚.
目的：本研究旨在探讨AD神经病理学是否会导致脊髓-膀胱轴自主神经功能障碍，这可能导致膀胱肌肉动力学的改变。
方法：我们在两个不同年龄使用了APPNL-G-F/NL-G-F敲入（APPKI）和APPwt/wt（野生型）小鼠，4-和10个月大，通过免疫组织化学研究AD如何影响膀胱组织功能，西方印迹,和药理学。
结果：我们表明，在10个月大的APPKI小鼠膀胱中，粘膜层与逼尿肌部分分离。尽管在APPKI膀胱中没有可检测到的淀粉样蛋白沉积，我们在APPKI腰脊髓中发现了淀粉样蛋白斑块。进一步的免疫印迹分析显示，酪氨酸羟化酶蛋白水平在4个月和10个月大的膀胱组织中显著降低，提示APPKI小鼠膀胱去甲肾上腺素合成减少。相比之下,β2肾上腺素能受体水平在4个月大而10个月大的APPKI膀胱中升高.在膀胱带中，肾上腺素能激动剂异丙肾上腺素在4个月而不是10个月大的APPKI膀胱中引起松弛增加。10Hz电场刺激，10个月大的APPKI膀胱条带比野生型对照更具反应性，在4个月大的APPKI膀胱中没有观察到差异。
结论：APPKI小鼠表现出LUTD，这可能是由脊髓中的淀粉样蛋白病理引起的，并导致突触前活动的成熟下降以及代偿性突触后上调。
目的：本研究旨在探讨AD神经病理学是否会导致脊髓-膀胱轴自主神经功能障碍，这可能导致膀胱肌肉动力学的改变。
方法：我们在两个不同年龄使用了APPNL-G-F/NL-G-F敲入（APPKI）和APPwt/wt（野生型）小鼠，4-和10个月大，通过免疫组织化学研究AD如何影响膀胱组织功能，西方印迹,和药理学。
结果：我们表明，在10个月大的APPKI小鼠膀胱中，粘膜层与逼尿肌部分分离。尽管在APPKI膀胱中没有可检测到的淀粉样蛋白沉积，我们在APPKI腰脊髓中发现了淀粉样蛋白斑块。进一步的免疫印迹分析显示，酪氨酸羟化酶蛋白水平在4个月和10个月大的膀胱组织中显著降低，提示APPKI小鼠膀胱去甲肾上腺素合成减少。相比之下,β2肾上腺素能受体水平在4个月大而10个月大的APPKI膀胱中升高.在膀胱带中，肾上腺素能激动剂异丙肾上腺素在4个月而不是10个月大的APPKI膀胱中引起松弛增加。10Hz电场刺激，10个月大的APPKI膀胱条带比野生型对照更具反应性，在4个月大的APPKI膀胱中没有观察到差异。
结论：APPKI小鼠表现出LUTD，这可能是由脊髓中的淀粉样蛋白病理引起的，并导致突触前活动的成熟下降以及代偿性突触后上调。
