Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the APP/Ld transgenic mouse model of Alzheimer's disease.
Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the APP/Ld transgenic mouse model of Alzheimer's disease.
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DOI：
10.1186/1750-1326-9-16
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发表时间：
2014-05-02
影响因子：
15.1
通讯作者：
Vassar R
中科院分区：
文献类型：
--
作者：
Kukreja L;Kujoth GC;Prolla TA;Van Leuven F;Vassar R
线粒体功能障碍的作用长期以来一直与年龄相关的脑病理学有关，包括阿尔茨海默病（AD）。然而，线粒体功能障碍可能导致AD神经退行性变的机制尚不清楚。为了在体内模拟线粒体功能障碍，我们利用了具有敲入突变的小鼠，该敲入突变使线粒体DNA聚合酶γ（PolgA D257 A）的校对功能失活，使得这些小鼠随着年龄的增长而积累线粒体DNA突变。PolgA D257 A小鼠出现无数线粒体生物能量缺陷和物理表型，模拟过早衰老，随后在一岁左右死亡。我们将D257 A小鼠与发展淀粉样蛋白斑块的完善的转基因AD小鼠模型（APP/Ld）杂交。我们假设线粒体功能障碍会影响Aβ的合成和/或清除，从而促进淀粉样蛋白生成并触发神经退行性变。最初，我们发现与APP/Ld单基因小鼠相比，D257 A; APP/Ld双基因小鼠中A β 42水平沿着Aβ42斑块密度增加。Aβ产生升高不是淀粉样蛋白病理学增加的原因，因为与APP/Ld小鼠相比，D257 A; APP/Ld小鼠中的BACE 1、PS1、C99和C83水平没有变化。然而，在具有D257 A突变的小鼠中，主要Aβ清除酶胰岛素降解酶（IDE）的水平降低，表明这是淀粉样蛋白负荷增加的机制。在APP转基因的存在下，D257 A小鼠也表现出明显的脑萎缩，伴有明显的皮质变薄，但没有明显的神经元损失。D257 A; APP/Ld小鼠具有增加的17 kDa裂解的半胱天冬酶-3和p25的水平，两者均指示神经变性。此外，D257 A; APP/Ld神经元出现形态学破坏，肿胀和空泡化的核。总体而言，我们的结果暗示PolgA D257 A突变和Aβ在引起神经退行性变中的作用之间存在协同作用。这些发现提供了对线粒体功能障碍机制的深入了解，线粒体功能障碍可能通过降低Aβ清除率而导致AD发病。
The role of mitochondrial dysfunction has long been implicated in age-related brain pathology, including Alzheimer’s disease (AD). However, the mechanism by which mitochondrial dysfunction may cause neurodegeneration in AD is unclear. To model mitochondrial dysfunction in vivo, we utilized mice that harbor a knockin mutation that inactivates the proofreading function of mitochondrial DNA polymerase γ (PolgA D257A), so that these mice accumulate mitochondrial DNA mutations with age. PolgA D257A mice develop a myriad of mitochondrial bioenergetic defects and physical phenotypes that mimic premature ageing, with subsequent death around one year of age. We crossed the D257A mice with a well-established transgenic AD mouse model (APP/Ld) that develops amyloid plaques. We hypothesized that mitochondrial dysfunction would affect Aβ synthesis and/or clearance, thus contributing to amyloidogenesis and triggering neurodegeneration. Initially, we discovered that Aβ42 levels along with Aβ42 plaque density were increased in D257A; APP/Ld bigenic mice compared to APP/Ld monogenic mice. Elevated Aβ production was not responsible for increased amyloid pathology, as levels of BACE1, PS1, C99, and C83 were unchanged in D257A; APP/Ld compared to APP/Ld mice. However, the levels of a major Aβ clearance enzyme, insulin degrading enzyme (IDE), were reduced in mice with the D257A mutation, suggesting this as mechanism for increased amyloid load. In the presence of the APP transgene, D257A mice also exhibited significant brain atrophy with apparent cortical thinning but no frank neuron loss. D257A; APP/Ld mice had increased levels of 17 kDa cleaved caspase-3 and p25, both indicative of neurodegeneration. Moreover, D257A; APP/Ld neurons appeared morphologically disrupted, with swollen and vacuolated nuclei. Overall, our results implicate synergism between the effects of the PolgA D257A mutation and Aβ in causing neurodegeneration. These findings provide insight into mechanisms of mitochondrial dysfunction that may contribute to the pathogenesis of AD via decreased clearance of Aβ.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
82.9
作者：
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