Department of Molecular Biochemistry, Cell Signalling, Ruhr University Bochum, 44801 Bochum, Germany.
Institute of Psychiatric Phenomics and Genomics (IPPG), LMU University Hospital, LMU Munich, 80336 Munich, Germany.
Int J Mol Sci. 2022 Apr 22;23(9):4656. doi: 10.3390/ijms23094656.
The β- and γ-secretase-driven cleavage of the amyloid precursor protein (APP) gives rise to the amyloid β peptide, which is believed to be the main driver of neurodegeneration in Alzheimer's disease (AD). As it is prominently detectable in extracellular plaques in post-mortem AD brain samples, research in recent decades focused on the pathological role of extracellular amyloid β aggregation, widely neglecting the potential meaning of very early generation of amyloid β inside the cell. In the last few years, the importance of intracellular amyloid β (iAβ) as a strong player in neurodegeneration has been indicated by a rising number of studies. In this review, iAβ is highlighted as a crucial APP cleavage fragment, able to manipulate intracellular pathways and foster neurodegeneration. We demonstrate its relevance as a pathological marker and shed light on initial studies aiming to modulate iAβ through pharmacological treatment, which has been shown to have beneficial effects on cognitive properties in animal models. Finally, we display the relevance of viral infections on iAβ generation and point out future directions urgently needed to manifest the potential relevance of iAβ in Alzheimer's disease.
β-和 γ-分泌酶驱动的淀粉样前体蛋白 (APP) 裂解产生淀粉样 β 肽，被认为是阿尔茨海默病 (AD) 神经退行性变的主要驱动因素。由于它在 AD 脑样本的死后外斑块中明显可检测到，因此近几十年来的研究集中在细胞外淀粉样 β 聚集的病理作用上，广泛忽略了细胞内淀粉样 β 早期生成的潜在意义。在过去的几年中，越来越多的研究表明细胞内淀粉样 β (iAβ) 作为神经退行性变的重要参与者的重要性。在这篇综述中，iAβ 被强调为一个关键的 APP 裂解片段，能够操纵细胞内途径并促进神经退行性变。我们证明了它作为病理标志物的相关性，并阐明了旨在通过药物治疗来调节 iAβ 的初步研究，这些研究已显示出对动物模型认知特性的有益影响。最后，我们展示了病毒感染对 iAβ 生成的相关性，并指出迫切需要确定 iAβ 在阿尔茨海默病中的潜在相关性的未来方向。
