School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia.
Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, South Australia.
J Neurochem. 2018 Feb;144(3):302-317. doi: 10.1111/jnc.14206. Epub 2017 Sep 27.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (Aβ) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Aβ. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both Aβ and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of Aβ and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of Aβ and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. Cover Image for this Issue: doi. 10.1111/jnc.14163.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是淀粉样β（Aβ）的进行性沉积和神经营养信号的失调，导致突触功能障碍、记忆丧失和细胞死亡。AD 患者大脑中 p75 神经生长因子受体的表达升高，表明其参与了这种疾病。然而，其作用的确切机制尚不清楚。在这里，我们表明 p75 与β-位淀粉样前体蛋白裂解酶-1（BACE1）相互作用，并且这种相互作用在存在 Aβ 的情况下增强。我们的结果表明，在皮质神经元中，存在 Aβ和 p75 时，BACE1 和淀粉样前体蛋白（APP）的共定位增加。此外，在存在 Aβ和 p75 的情况下，APP 和 BACE1 在早期内体中的定位增加。在存在 Aβ和 p75 的情况下，c-Jun N 端激酶（JNK）对 APP-Thr668 和 BACE1-Ser498 的磷酸化增加可能是导致这种定位的原因。总之，我们的研究提出了 p75 可能参与淀粉样蛋白形成的可能性，这可能代表 AD 的未来治疗靶点。本期的封面图片：doi.10.1111/jnc.14163.
