Annexin A6 membrane repair protein protects against amyloid-induced dystrophic neurites and tau phosphorylation in Alzheimer’s disease model mice

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY
Katherine R. Sadleir, Karen P. Gomez, Abigail E. Edwards, Armana J. Patel, Makenna L. Ley, Ammaarah W. Khatri, Joanna Guo, Shreya Mahesh, Elyse A. Watkins, Jelena Popovic, Devi Krishna Priya Karunakaran, Dmitry Prokopenko, Rudolph E. Tanzi, Bernabe Bustos, Steven J. Lubbe, Alexis R. Demonbruen, Elizabeth M. McNally, Robert Vassar
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引用次数: 0

Abstract

In Alzheimer’s disease, accumulation of amyloid-β (Aβ) peptide is thought to cause formation of neurofibrillary tangles composed of hyperphosphorylated tau protein, which correlates with neuronal loss and cognitive impairment, but the mechanism linking Aβ and tau pathologies is unknown. Dystrophic neurites, which surround Aβ plaques and accumulate phosphorylated tau and other proteins, may play a role in seeding and spreading of pathologic tau. Here, we investigate the novel hypothesis that improved membrane repair capacity decreases dystrophic neurite formation by protecting axons from Aβ-induced membrane damage. Using a ratiometric calcium sensor and a FRET-based calpain cleavage sensor, we demonstrate that dystrophic neurites in 5XFAD mice have elevated resting calcium levels and calpain activity because of putative membrane damage. Annexin A6, a plasma membrane repair in muscle and neurons, is present at plasma membrane of neurons and dystrophic neurites in murine and human brains. Overexpression of annexin A6 in brains of 5XFAD mice decreased size and quantity of dystrophic neurites and accumulation of phospho-tau181, an early biomarker of amyloid pathology. Phospho-tau231, another early amyloid biomarker, and phosphorylated of tau kinases, c-jun N-terminal kinase (JNK) and Calmodulin Kinase II (CaMKII) accumulate in dystrophic neurites in the brains of amyloid pathology mice and humans with AD, suggesting that dystrophic neurites are sites of active tau phosphorylation. Overexpression of dominant-negative annexin A6 in 5XFAD mice increased dystrophic neurites and phospho-tau181. Intracerebral injection of recombinant annexin A6 in 5XFAD and APP-NLGF knock-in mice resulted in localization of recombinant A6 to membranes of dystrophic neurites, suggesting therapeutic potential of recombinant annexin A6 for AD. In conclusion, dystrophic neurites have Aβ-induced membrane damage characterized by calcium elevation, calpain activation, and accumulation of tau kinases and phosphorylated tau. Overexpression of annexin A6 reduces dystrophic neurites and phospho-tau accumulation, suggesting that annexin A6-mediated membrane repair may represent a novel therapeutic approach for AD.

膜联蛋白A6膜修复蛋白对阿尔茨海默病模型小鼠淀粉样蛋白诱导的营养不良神经突和tau磷酸化具有保护作用
在阿尔茨海默病中,淀粉样蛋白-β (Aβ)肽的积累被认为导致由过度磷酸化的tau蛋白组成的神经原纤维缠结的形成,这与神经元丢失和认知障碍有关,但Aβ和tau病理之间的联系机制尚不清楚。营养不良的神经突围绕在a β斑块周围,积累磷酸化的tau和其他蛋白质,可能在病理性tau的播种和扩散中起作用。在这里,我们研究了一种新的假设,即膜修复能力的提高通过保护轴突免受a β诱导的膜损伤来减少营养不良神经突的形成。使用比例钙传感器和基于fret的钙蛋白酶裂解传感器,我们证明5XFAD小鼠的营养不良神经突由于假定的膜损伤而升高了静息钙水平和钙蛋白酶活性。膜联蛋白A6是一种肌肉和神经元的质膜修复蛋白,存在于鼠脑和人脑的神经元和营养不良的神经突的质膜上。5XFAD小鼠大脑中膜联蛋白A6的过度表达减少了营养不良神经突的大小和数量以及磷酸化tau181(淀粉样蛋白病理的早期生物标志物)的积累。Phospho-tau231是另一种早期淀粉样蛋白生物标志物,磷酸化tau激酶、c-jun n -末端激酶(JNK)和钙调蛋白激酶II (CaMKII)在淀粉样蛋白病理小鼠和AD患者的大脑营养不良的神经突中积累,表明营养不良的神经突是tau活性磷酸化的位点。5XFAD小鼠中显性阴性膜联蛋白A6的过表达增加了营养不良的神经突和磷酸化tau181。5XFAD和APP-NLGF敲入小鼠脑内注射重组膜联蛋白A6,重组膜联蛋白A6定位于营养不良的神经突膜,提示重组膜联蛋白A6治疗AD的潜力。综上所述,营养不良的神经突具有a β诱导的膜损伤,其特征是钙升高、钙蛋白酶激活、tau激酶和磷酸化tau的积累。膜联蛋白A6的过表达减少了营养不良的神经突和磷酸化tau蛋白的积累,这表明膜联蛋白A6介导的膜修复可能是一种新的治疗AD的方法。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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