Hoozemans Jeroen J M, van Haastert Elise S, Nijholt Diana A T, Rozemuller Annemieke J M, Eikelenboom Piet, Scheper Wiep
VU University Medical Center, Department of Pathology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
Am J Pathol. 2009 Apr;174(4):1241-51. doi: 10.2353/ajpath.2009.080814. Epub 2009 Mar 5.
Accumulation of misfolded proteins in the endoplasmic reticulum triggers a cellular stress response called the unfolded protein response (UPR) that protects the cell against the toxic buildup of misfolded proteins. Previously, we reported that UPR activation is increased in Alzheimer's disease (AD) patients. How the UPR relates to the pathological hallmarks of AD is still elusive. In the present study, the involvement of UPR activation in neurofibrillary degeneration in AD was investigated. Immunoreactivity for the phosphorylated UPR activation markers pancreatic ER kinase (pPERK), eukaryotic initiation factor 2alpha, and inositol-requiring enzyme 1alpha was observed in hippocampal neurons associated with granulovacuolar degeneration. The percentage of pPERK-immunoreactive neurons was increased in AD cases compared with nondemented control cases and with the Braak stage for neurofibrillary changes. Although absent from neurofibrillary tangles, pPERK immunoreactivity was most abundant in neurons with diffuse localization of phosphorylated tau protein. Additional analyses showed that pPERK immunoreactivity was associated with ubiquitin and the ubiquitin binding protein p62. A strong co-occurrence of immunoreactivity for both pPERK and glycogen synthase kinase 3beta in neurons was also observed. Together, these data indicate that UPR activation in AD neurons occurs at an early stage of neurofibrillary degeneration and suggest that the prolonged activation of the UPR is involved in both tau phosphorylation and neurodegeneration in AD pathogenesis.
内质网中错误折叠蛋白的积累会引发一种称为未折叠蛋白反应（UPR）的细胞应激反应，该反应可保护细胞免受错误折叠蛋白的毒性积累影响。此前，我们报道过阿尔茨海默病（AD）患者中UPR激活增加。UPR与AD的病理特征之间的关系仍不清楚。在本研究中，我们调查了UPR激活在AD神经原纤维变性中的作用。在与颗粒空泡变性相关的海马神经元中观察到了磷酸化的UPR激活标志物胰腺内质网激酶（pPERK）、真核起始因子2α和肌醇需求酶1α的免疫反应性。与非痴呆对照病例以及神经原纤维变化的Braak分期相比，AD病例中pPERK免疫反应性神经元的百分比增加。尽管神经原纤维缠结中没有，但pPERK免疫反应性在磷酸化tau蛋白呈弥漫性定位的神经元中最为丰富。进一步分析表明，pPERK免疫反应性与泛素及泛素结合蛋白p62相关。在神经元中还观察到pPERK和糖原合酶激酶3β的免疫反应性强烈共现。总之，这些数据表明AD神经元中的UPR激活发生在神经原纤维变性的早期阶段，并提示UPR的长期激活参与了AD发病机制中的tau磷酸化和神经变性过程。
