Briggs Clark A, Chakroborty Shreaya, Stutzmann Grace E
Department of Neuroscience, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago, IL 60064, USA.
Department of Neuroscience, Rosalind Franklin University of Medicine and Science, The Chicago Medical School, North Chicago, IL 60064, USA.
Biochem Biophys Res Commun. 2017 Feb 19;483(4):988-997. doi: 10.1016/j.bbrc.2016.09.088. Epub 2016 Sep 20.
The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca signaling disruptions, and focus on its role in driving synaptic deficits - which is the feature that does correlate with AD-associated memory loss. Excess Carelease from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IPR and RyR, and the recent emphasis on RyR2. Consistent with ER Ca mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.
在某些方面，AD研究领域的当前状态极具动态性，而在其他方面似乎停滞不前。关于前者，我们目前对疾病起始机制缺乏了解、缺乏有效的治疗选择以及AD患者数量的不断增加，正在推动新的研究方向，包括急需重新关注早期致病机制、验证新靶点以及研究相关生物标志物，以及其他抑制疾病进展并首要保护记忆功能的令人兴奋的新努力。关于后者，最近针对Aβ和APP加工的一系列III期临床试验失败令人失望，再加上脑Aβ水平与认知功能之间的关联性较差，导致许多人呼吁重新评估淀粉样蛋白级联假说的首要地位。在本综述中，我们整合了对AD发病机制中最早描述的信号异常之一，即细胞内钙信号破坏的新见解，并关注其在驱动突触缺陷中的作用——这是与AD相关的记忆丧失相关的特征。内质网（ER）等细胞内储存库中过量的钙释放已在AD的细胞和动物模型以及人类患者中得到充分描述，在此我们详述了ER定位释放通道（如IPR和RyR）的最新进展，以及最近对RyR2的关注。与AD中ER钙处理不当一致的是最近涉及SOCE方面的发现，如STIM2功能以及TRPC3和TRPC6水平。还讨论了在信号传导和蛋白质处理中重要的其他钙调节细胞器，并对溶酶体调节提出了新观点。这些早期信号异常在突触病理生理学和突触可塑性破坏的背景下进行了讨论，特别强调了短期可塑性缺陷。总体而言，我们旨在更新和扩展与AD发病机制相关的早期神经元信号异常列表，确定涉及的特定通道和细胞器，并将这些与驱动AD记忆丧失的近端突触损伤联系起来。这一切都在确定新的治疗靶点以保护AD患者认知功能这一更广泛的目标范围内。
