Gain-of-function somatic mutations contribute to inflammation and blood vessel damage that lead to Alzheimer dementia: a hypothesis
Gain-of-function somatic mutations contribute to inflammation and blood vessel damage that lead to Alzheimer dementia: a hypothesis
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DOI：
10.1096/fj.15-282285
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发表时间：
2016-02-01
期刊：
影响因子：
4.8
通讯作者：
Marchesi, Vincent T.
中科院分区：
文献类型：
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作者：
Marchesi, Vincent T.
淀粉样蛋白沉积是晚期阿尔茨海默氏症（AD）的一个特征，但它们是该疾病的开端还是其结果仍然是一个悬而未决的问题。为了探索另一种致病机制，我提出开始致病级联的触发事件不是淀粉样蛋白沉积，而是由炎症反应引起的血管损伤，导致缺血、淀粉样蛋白积累、轴突变性、突触丧失，最终导致不可逆转的神经元细胞死亡。炎症和血管损伤是公认的阿尔茨海默病的并发症，但导致它们的原因以及大脑微血管受到影响的原因从未得到充分解决。由于已知NLRP3、APP、TREX1、NOTCH3和Col4A1的遗传性常染色体显性突变会引发炎症反应，并在多种疾病中损害大脑，因此我认为，同一5个基因家族的一个或多个低丰度、功能获得性体细胞突变会损害大脑微血管，从而导致痴呆。这意味着导致阿尔茨海默病的致病诱因不是来自外部入侵者或淀粉样蛋白，而是来自我们自身基因的氧化损伤。
Amyloid deposits are a characteristic feature of advanced Alzheimer dementia (AD), but whether they initiate the disease or are a consequence of it remains an unsettled question. To explore an alternative pathogenic-mechanism, I propose that the triggering events that begin the pathogenic cascade are not amyloid deposits but damaged blood vessels caused by inflammatory reactions that lead to ischemia, amyloid accumulation, axonal degeneration, synaptic loss, and eventually irreversible neuronal cell death. Inflammation and blood vessel damage are well recognized complications of AD, but what causes them and why the cerebral microvasculature is affected have never been adequately addressed. Because heritable autosomal dominant mutations of NLRP3, APP, TREX1, NOTCH3, and Col4A1 are known to provoke inflammatory reactions and damage the brain in a wide variety of diseases, I propose that one or more low abundant, gain-of-function somatic mutations of the same 5 gene families damage the microvasculature of the brain that leads to dementia. This implies that the pathogenic triggers that lead to AD are derived not from external invaders or amyloid but from oxidative damage of our own genes.