Interaction between NH2-tau fragment and Aβ in Alzheimer's disease mitochondria contributes to the synaptic deterioration
Interaction between NH2-tau fragment and Aβ in Alzheimer's disease mitochondria contributes to the synaptic deterioration
复制标题
DOI：
10.1016/j.neurobiolaging.2011.08.001
复制
发表时间：
2012-04-01
影响因子：
4.2
通讯作者：
Calissano, Pietro
中科院分区：
文献类型：
--
作者：
Amadoro, Giuseppina;Corsetti, Veronica;Calissano, Pietro
尽管β淀粉样蛋白（A β）肽可以促进tau病理，其毒性同时依赖于tau，但这些蛋白在体内相互作用的潜在机制仍未得到解决。结构和功能线粒体改变在阿尔茨海默病（AD）发病机制的突触衰竭中起着早期的促进作用，并且在携带斑块和缠结的三重APP/PS/tau转基因小鼠中，与单独过表达tau或淀粉样蛋白前体蛋白（APP）的小鼠相比，线粒体损伤加重。在这里,我们发现一个神经毒性氨基末端（NH2）衍生的tau片段位于人类tau40亚型的26到230个氨基酸之间（441个氨基酸），但不是生理全长蛋白，优先与人类AD突触中与线粒体腺嘌呤核苷酸易位子-1 （ANT-1）和亲环蛋白d相关的β肽相互作用。两个肽- β 1-42和最长的20-22 kDa NH2-tau片段的更小且更有效的NH2-26-44肽-抑制ANT-1依赖性二磷酸腺苷-三磷酸腺苷（ADP/ATP）分别以非竞争性和竞争性方式交换，并通过加剧ANT-1损伤进一步加重线粒体功能障碍。综上所述，这些数据建立了病理性APP和tau产物对突触线粒体的共同、直接和协同毒性，并为联合、更有效地干预阿尔茨海默病早期突触功能障碍提供了潜在的、新的途径和靶点。(C) 2012爱思唯尔公司版权所有。
Although amyloid beta (A beta) peptide can promote tau pathology and its toxicity is concurrently tau-dependent, the underlying mechanisms of the in vivo interplay of these proteins remain unsolved. Structural and functional mitochondrial alterations play an early, precipitating role in synaptic failure of Alzheimer's disease (AD) pathogenesis and an aggravated mitochondrial impairment has been described in triple APP/PS/tau transgenic mice carrying both plaques and tangles, if compared with mice overexpressing tau or amyloid precursor protein (APP) alone. Here, we show that a neurotoxic aminoterminal (NH2)-derived tau fragment mapping between 26 and 230 amino acids of the human tau40 isoform (441 amino acids)-but not the physiological full-length protein-preferentially interacts with A beta peptide(s) in human AD synapses in association with mitochondrial adenine nucleotide translocator-1 (ANT-1) and cyclophilin D. The two peptides-A beta 1-42 and the smaller and more potent NH2-26-44 peptide of the longest 20-22 kDa NH2-tau fragment-inhibit the ANT-1-dependent adenosine diphosphate-adenosine triphosphate (ADP/ATP) exchange in a noncompetitive and competitive manner, respectively, and together further aggravate the mitochondrial dysfunction by exacerbating the ANT-1 impairment. Taken together, these data establish a common, direct and synergistic toxicity of pathological APP and tau products on synaptic mitochondria and suggest potential, new pathway(s) and target(s) for a combined, more efficient therapeutic intervention of early synaptic dysfunction in AD. (C) 2012 Elsevier Inc. All rights reserved.