Department of Neuroscience, MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK.
Neurobiol Dis. 2011 Jun;42(3):349-59. doi: 10.1016/j.nbd.2011.01.028. Epub 2011 Feb 17.
Niemann-Pick type C disease (NPC) is a lysosomal storage disorder which, at the cellular level, shows amyloid Aβ 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 Aβ, 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.
尼曼-匹克 C 型病（NPC）是一种溶酶体贮积症，在细胞水平上显示出与 AD 大脑中相似的淀粉样 Aβ 和 tau 病理学。在这里，我们在 NPC 的小鼠模型中研究了消除 Aβ 的来源，即 APP，对疾病表型以及 tau 的表达水平和磷酸化模式的影响。我们推断，从 NPC 大脑中去除 APP 可能有助于揭示其对疾病表型的影响，并阐明 APP 功能与 tau 动态平衡之间的生理和病理相互作用的机制，至少在 NPC 中是这样。我们发现，出乎意料的是，APP 在 NPC 小鼠中的缺失导致神经肌肉协调性更差和累积存活率降低；胆固醇异常加剧；星形胶质细胞增多和 tau 动态平衡失调。我们的结果与 NPC 和 AD 大脑中的神经退行性变机制一致，其中胆固醇失调是影响 tau 动态平衡的关键早期致病事件，与淀粉样蛋白积累平行且独立。
