Loss of amyloid precursor protein in a mouse model of Niemann-Pick type C disease exacerbates its phenotype and disrupts tau homeostasis
Loss of amyloid precursor protein in a mouse model of Niemann-Pick type C disease exacerbates its phenotype and disrupts tau homeostasis
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DOI：
10.1016/j.nbd.2011.01.028
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发表时间：
2011-06-01
影响因子：
6.1
通讯作者：
Soriano, Salvador
中科院分区：
文献类型：
--
作者：
Nunes, Ana;Pressey, Sarah N. R.;Soriano, Salvador
尼曼-皮克C型病（NPC）是一种溶酶体贮积障碍，在细胞水平上，表现出淀粉样蛋白a β和tau病变，与AD脑中的病变相似。在这里，我们研究了在NPC小鼠模型中，去除a β的来源，即APP，对疾病表型和tau的表达水平和磷酸化模式的影响。我们推断，从鼻咽癌大脑中移除APP可能有助于揭示其对疾病表型的影响，并阐明APP功能和tau稳态之间生理和病理相互作用的机制，至少在鼻咽癌中如此。我们发现，出乎意料的是，NPC小鼠APP的缺失会导致神经肌肉协调性和累积存活率下降；胆固醇异常加重；星形细胞增多和tau体内平衡失调。我们的结果与NPC和AD大脑神经退行性变的机制一致，其中胆固醇失调是影响tau稳态的关键早期致病事件，与淀粉样蛋白积累平行，独立于淀粉样蛋白积累。(c) 2011爱思唯尔公司版权所有。
Niemann-Pick type C disease (NPC) is a lysosomal storage disorder which, at the cellular level, shows amyloid A beta and tau pathologies comparable to those seen in the AD brain. Here, we have investigated, in a mouse model of NPC, the impact of removing the source of A beta, namely APP, on the disease phenotype and on the expression levels and phosphorylation patterns of tau. We reasoned that removing APP from the NPC brain might help to unveil its impact on the disease phenotype and shed light on the mechanisms governing the interaction, both physiological and pathological, between APP function and tau homeostasis, at least in NPC. We show that, unexpectedly, loss of APP in NPC mice leads to poorer neuromuscular coordination and cumulative survival rates; exacerbation of their cholesterol abnormalities; higher levels of astrocytosis and dysregulation of tau homeostasis. Our results are consistent with a mechanism of neurodegeneration in the NPC and AD brains in which cholesterol dysregulation is a key early pathogenic event affecting tau homeostasis in parallel with, and independently of, amyloid accumulation. (c) 2011 Elsevier Inc. All rights reserved.