Pinnock Emma C, Jovanovic Katarina, Pinto Maxine G, Ferreira Eloise, Dias Bianca Da Costa, Penny Clement, Knackmuss Stefan, Reusch Uwe, Little Melvyn, Schatzl Hermann M, Weiss Stefan F T
School of Molecular and Cell Biology, University of the Witwatersrand, Wits, Johannesburg, Republic of South Africa (RSA).
Department of Internal Medicine, University of the Witwatersrand, Johannesburg, Parktown, Republic of South Africa (RSA).
J Alzheimers Dis. 2016;49(3):645-57. doi: 10.3233/JAD-150482.
The neuronal perturbations in Alzheimer's disease are attributed to the formation of extracellular amyloid-β (Aβ) neuritic plaques, composed predominantly of the neurotoxic Aβ42 isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Aβ42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Aβ42 shedding and Aβ42-induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Aβ42, the mechanism underlying this cytotoxicity may be indirectly due to the PrPc-Aβ42 interaction with LRP/LR. The effects of this interaction were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assays. PrPc overexpression significantly enhanced Aβ42 cytotoxicity in vitro, while PrP-/- cells were more resistant to the cytotoxic effects of Aβ42 and exhibited significantly less cell death than PrPc expressing N2a cells. Although anti-LRP/LR specific antibody IgG1-iS18 significantly enhanced cell viability in both pSFV1-huPrP1-253 transfected and non-transfected cells treated with exogenous Aβ42, it failed to have any cell rescuing effect in PrP-/- HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Aβ42-PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer's disease.
阿尔茨海默病中的神经元紊乱归因于细胞外淀粉样β（Aβ）神经炎性斑块的形成，这些斑块主要由具有神经毒性的Aβ42异构体组成。尽管这些斑块已被证明在突触功能障碍中起作用，但神经元细胞毒性一直被认为是由可溶性Aβ42寡聚体引起的。37kDa/67kDa层粘连蛋白受体与Aβ42的脱落、Aβ42诱导的神经元细胞毒性以及这种神经毒性肽的内化有关。由于细胞朊蛋白与LRP/LR和Aβ42都结合，这种细胞毒性的潜在机制可能间接归因于PrPc-Aβ42与LRP/LR的相互作用。通过3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四氮唑溴盐试验研究了这种相互作用的影响。PrPc的过表达在体外显著增强了Aβ42的细胞毒性，而PrP-/-细胞对Aβ42的细胞毒性更具抗性，并且与表达PrPc的N2a细胞相比，细胞死亡明显更少。尽管抗LRP/LR特异性抗体IgG1-iS18在转染了pSFV1-huPrP1-253的细胞和用外源性Aβ42处理的未转染细胞中均显著提高了细胞活力，但它在PrP-/-HpL3-4细胞中没有任何细胞拯救作用。这些结果表明，LRP/LR在Aβ42-PrPc介导的细胞毒性中起重要作用，并且抗LRP/LR特异性抗体可能作为阿尔茨海默病的潜在治疗工具。
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