Bhattacharya Antaripa, Izzo Antonella, Mollo Nunzia, Napolitano Filomena, Limone Adriana, Margheri Francesca, Mocali Alessandra, Minopoli Giuseppina, Lo Bianco Alessandra, Di Maggio Federica, D'Argenio Valeria, Montuori Nunzia, Lavecchia Antonio, Sarnataro Daniela
Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via S. Pansini 5, 80131 Naples, Italy.
Department of Translational Medical Sciences, University of Naples "Federico II", Via S. Pansini 5, 80131 Naples, Italy.
J Pers Med. 2020 Nov 16;10(4):232. doi: 10.3390/jpm10040232.
Alzheimer's disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aβ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, Aβ and 37/67kDa laminin receptor (LR), finding the possibility to regulate intracellular APP localization and maturation through modulation of the receptor. Here, we report that in fibroblasts from familial AD (fAD), APP was prevalently expressed as an immature isoform and accumulated preferentially in the transferrin-positive recycling compartment rather than in the Golgi apparatus. Moreover, besides the altered mitochondrial network exhibited by fAD patient cells, the levels of pAkt and pGSK3 were reduced in respect to healthy control fibroblasts and were accompanied by an increased amount of secreted Aβ in conditioned medium from cell cultures. Interestingly, these features were reversed by inhibition of 37/67kDa LR by NSC47924 a small molecule that was able to rescue the "typical" APP localization in the Golgi apparatus, with consequences on the Aβ level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and Aβ levels with implications in Alzheimer's disease.
阿尔茨海默病（AD）是一种由蛋白质错误折叠和聚集引起的致命性神经退行性疾病，会影响脑功能并导致痴呆。淀粉样前体蛋白（APP）经β-和γ-分泌酶切割产生的肽——淀粉样β蛋白（Aβ），被认为是AD的病理标志。我们之前的研究以及多条证据表明，APP、Aβ与37/67kDa层粘连蛋白受体（LR）之间存在紧密联系，发现有可能通过调节该受体来调控细胞内APP的定位和成熟。在此，我们报告，在家族性AD（fAD）患者的成纤维细胞中，APP主要以未成熟异构体的形式表达，并优先积聚在转铁蛋白阳性的再循环区室中，而非高尔基体。此外，除了fAD患者细胞中线粒体网络发生改变外，与健康对照成纤维细胞相比，fAD患者细胞中磷酸化Akt（pAkt）和磷酸化糖原合成酶激酶3（pGSK3）的水平降低，并且细胞培养条件培养基中分泌的Aβ量增加。有趣的是，小分子NSC47924抑制37/67kDa LR后，这些特征发生了逆转，该小分子能够挽救APP在高尔基体中的“典型”定位，并对Aβ水平和线粒体网络产生影响。总之，这些发现表明，调节37/67kDa LR可能是控制APP转运和Aβ水平的有用工具，对阿尔茨海默病具有重要意义。
