Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer's disease.
Stabilizing ER Ca2+ channel function as an early preventative strategy for Alzheimer's disease.
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DOI：
10.1371/journal.pone.0052056
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Stutzmann GE
中科院分区：
文献类型：
--
作者：
Chakroborty S;Briggs C;Miller MB;Goussakov I;Schneider C;Kim J;Wicks J;Richardson JC;Conklin V;Cameransi BG;Stutzmann GE
阿尔茨海默病(AD)是一种毁灭性的神经退行性疾病，目前尚无治愈方法。虽然目前的治疗针对的是晚期淀粉样蛋白形成和胆碱能张力，但到目前为止，这些策略在防止疾病进展方面被证明是无效的。造成这种情况的原因可能是多种多样的，可能反映了较晚的干预，或者是早期的致病机制被忽视而被允许加速疾病进程。一个这样的例子包括突触病理，这是一种与认知障碍密切相关的疾病组成部分。钙稳态失调可能是导致突触功能障碍的关键因素之一。突变型早老素(PS)AD小鼠最早的病理生理指标之一是细胞内钙信号增加，主要是通过ER定位的三磷酸肌醇(IP3)和兰尼定受体(RyR)。特别是，RyR介导的突触内钙上调与早期(症状前)AD阶段突触内稳态的改变和网络抑制有关。在这里，我们提供了一种替代治疗AD的方法，通过稳定与突触异常相关的早期致病机制。我们将RyR作为一种防止疾病进展的手段，并用RyR抑制剂丹曲林的新配方亚慢性治疗AD小鼠模型(4周)。使用双光子钙成像和膜片钳记录，我们证明丹曲林治疗在早期和晚期AD小鼠的海马片中完全正常化躯体和树突室内的ER钙信号。此外，通过丹曲林治疗，AD小鼠中升高的RyR2水平恢复到对照水平，突触传递和突触可塑性也恢复到正常水平。丹曲林治疗的AD小鼠大脑皮质和海马区的β沉积也减少。在这项研究中，我们强调了钙离子异常在AD中的关键作用，并提出了一种新的策略来保护早期AD患者的突触功能，从而保护认知功能。
Alzheimer’s disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca2+ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca2+ signaling, predominantly through the ER-localized inositol triphosphate (IP3) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca2+ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca2+ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca2+ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients.
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影响因子：
2
作者：
Howlett, D. R.;Bowler, K.;Richardson, J. C.
通讯作者：
Richardson, J. C.
影响因子：
4
作者：
Ferreira, I. L.;Bajouco, L. M.;Rego, A. C.
通讯作者：
Rego, A. C.
钙离子促进形成淀粉样β肽（1-40）的寡聚物，该低聚物因果关系与阿尔茨海默氏病的神经元毒性有关。
影响因子：
3.7
作者：
Itkin A;Dupres V;Dufrêne YF;Bechinger B;Ruysschaert JM;Raussens V
通讯作者：
Raussens V
影响因子：
4.2
作者：
Bruno AM;Huang JY;Bennett DA;Marr RA;Hastings ML;Stutzmann GE
通讯作者：
Stutzmann GE
影响因子：
2.9
作者：
Howlett, DR;Richardson, JC;Gonzalez, MI
通讯作者：
Gonzalez, MI