High mitochondrial calcium levels precede neuronal death in vivo in Alzheimer's disease
High mitochondrial calcium levels precede neuronal death in vivo in Alzheimer's disease
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DOI：
10.15698/cst2020.07.226
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发表时间：
2020-07-01
期刊：
影响因子：
6.4
通讯作者：
Bacskai, Brian J.
中科院分区：
文献类型：
--
作者：
Calvo-Rodriguez, Maria;Bacskai, Brian J.
阿尔茨海默病（AD）是痴呆症的最常见原因，影响着全世界数百万人。AD的神经毒性机制包括钙（Ca 2+）稳态受损和线粒体功能障碍，两者均导致神经元损伤。很少有人知道确切的线粒体Ca 2+稳态在活的大脑，特别是在AD。直到现在，随着活体成像技术和转基因小鼠模型的发展，我们才能够直接观察细胞特定区域或特定亚细胞区室（如线粒体）中的Ca 2+水平。使用多光子显微镜，靶向线粒体的Ca（2+）报告基因和脑β淀粉样变性（APP/PS1）的小鼠模型，我们最近的研究（Nat Comms 2020，11：2146）发现转基因小鼠在斑块沉积后，以及在将天然可溶性淀粉样蛋白β（A β）寡聚体以与人脑中发现的浓度相似的浓度局部应用于健康小鼠脑后，线粒体Ca 2+浓度升高。线粒体中Ca 2+升高先于神经元死亡，可作为AD神经保护治疗的靶点。在这里，我们描述了我们的主要研究结果，并提出了新的问题，为未来的研究，旨在更好地了解线粒体Ca 2+稳态异常的AD。
Alzheimer's disease (AD), the most common cause of dementia, affects millions of people worldwide. Suggested mechanisms of neurotoxicity in AD include impaired calcium (Ca2+) homeostasis and mitochondrial dysfunction, both contributing to neuronal damage. Little was known about the exact mitochondrial Ca2+ homeostasis in the living brain, particularly in AD. Only now, with the development of intravital imaging techniques and transgenic mouse models of the disease, we are able to directly observe Ca2+ levels in specific regions or particular subcellular compartments of cells, such as mitochondria. Using multiphoton microscopy, a Ca(2+ )reporter targeted to mitochondria and a mouse model of cerebral beta amyloidosis (APP/PS1), our recent study (Nat Comms 2020, 11:2146) found elevated mitochondrial Ca2+ concentration in the transgenic mouse after plaque deposition, and after topical application of natural soluble amyloid beta (A beta) oligomers to the healthy mouse brain at concentrations similar to those found in the human brain. Elevated Ca2+ in mitochondria preceded neuronal death and could be targeted for neuroprotective therapies in AD. Here, we describe our main findings and pose new questions for future studies aimed at better understanding mitochondrial Ca2+ dyshomeostasis in AD.