Vogelgesang Silke, Glatzel Markus, Walker Lary C, Kroemer Heyo K, Aguzzi Adriano, Warzok Rolf W
Department of Neuropathology, University of Greifswald, 17487, Greifswald, Germany.
Acta Neuropathol. 2006 May;111(5):436-43. doi: 10.1007/s00401-006-0042-3. Epub 2006 Mar 7.
The abnormal conformation and assembly of proteins in the central nervous system is increasingly thought to be a critical pathogenic mechanism in neurodegenerative disorders such as Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease (AD). CJD is marked primarily by the buildup of misfolded prion protein (PrP(Sc)) in brain, whereas the accrual of beta-amyloid protein (Abeta) and tau protein are characteristic for AD. Prior studies have shown that the ATP-binding cassette transporter P-glycoprotein (P-gp) is a cellular efflux pump for Abeta, and that age-associated deficits in P-gp may be involved in the pathogenesis of Alzheimer's disease. In the present study, we investigated the relationship between P-gp and idiopathic CJD, and found that CJD, like AD, is associated with a decrease in the expression of cerebrovascular P-gp. In some instances, Abeta and PrP deposits coexist in cases of CJD, suggesting the possibility of pathogenic interactions. Since there is, to date, no evidence that PrP itself is a substrate for P-gp, we hypothesize that the age-related deficits in P-gp could promote the accumulation of PrP(Sc) either by promoting the buildup of Abeta (which could act as a seed for the aggregation of PrP(Sc)), or by overloading the ubiquitin-proteasomal catabolic system, and thereby facilitating the accumulation of PrP. Alternatively, the loss of P-gp could be a non-specific response to neurodegenerative changes in the central nervous system. In either case, dysfunction of this critical toxin-elimination pathway in CJD and AD suggests that selectively increasing cerebrovascular P-gp function could open new therapeutic pathways for the prevention and/or treatment of a number of proteopathic disorders of the central nervous system.
中枢神经系统中蛋白质的异常构象和组装越来越被认为是诸如克雅氏病（CJD）和阿尔茨海默病（AD）等神经退行性疾病的关键致病机制。CJD的主要特征是大脑中错误折叠的朊病毒蛋白（PrP(Sc)）的积累，而β-淀粉样蛋白（Aβ）和tau蛋白的积累是AD的特征。先前的研究表明，ATP结合盒转运体P-糖蛋白（P-gp）是Aβ的细胞外排泵，且P-gp与年龄相关的缺陷可能参与阿尔茨海默病的发病机制。在本研究中，我们调查了P-gp与散发性CJD之间的关系，发现CJD与AD一样，与脑血管P-gp表达的降低有关。在某些情况下，CJD病例中Aβ和PrP沉积物共存，提示存在致病相互作用的可能性。由于迄今为止没有证据表明PrP本身是P-gp的底物，我们推测与年龄相关的P-gp缺陷可能通过促进Aβ的积累（其可作为PrP(Sc)聚集的种子）或使泛素-蛋白酶体分解代谢系统过载，从而促进PrP(Sc)的积累，进而促进PrP的积累。或者，P-gp的丧失可能是对中枢神经系统神经退行性变化的非特异性反应。无论哪种情况，CJD和AD中这种关键毒素清除途径的功能障碍表明，选择性增加脑血管P-gp功能可能为预防和/或治疗一些中枢神经系统的蛋白病开辟新的治疗途径。
