High mitochondrial calcium levels precede neuronal death in vivo in Alzheimer's disease.

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2020-06-18 DOI:10.15698/cst2020.07.226
Maria Calvo-Rodriguez, Brian J Bacskai
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引用次数: 11

Abstract

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 Ca2+ reporter targeted to mitochondria and a mouse model of cerebral β 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 (Aβ) 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.

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阿尔茨海默病患者体内高线粒体钙水平先于神经元死亡。
阿尔茨海默病(AD)是痴呆症最常见的病因,影响着全世界数百万人。阿尔茨海默病的神经毒性机制包括钙(Ca2+)稳态受损和线粒体功能障碍,两者都有助于神经元损伤。人们对活体大脑中确切的线粒体Ca2+稳态知之甚少,特别是在阿尔茨海默病中。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到特定区域或特定亚细胞区室(如线粒体)中的Ca2+水平。我们最近的研究(Nat Comms 2020, 11:21 146)使用多光子显微镜,针对线粒体的Ca2+报告细胞和脑β淀粉样变性小鼠模型(APP/PS1),发现斑块沉积后转基因小鼠线粒体Ca2+浓度升高,并且在健康小鼠大脑局部应用天然可溶性β淀粉样蛋白(a β)低聚物后,其浓度与人脑中的浓度相似。线粒体中Ca2+的升高在神经元死亡之前,可能是AD神经保护治疗的目标。在这里,我们描述了我们的主要发现,并为未来的研究提出了新的问题,旨在更好地理解AD中线粒体Ca2+失衡。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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