Spreading of amyloid-尾 peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance

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• 作者：Jakob Domert^a ; Sahana Bhima Rao^a ; Lotta Agholme^a ; Ann-Christin Brorsson^b ; Jan Marcusson^c ; Martin Hallbeck^a ; ^d ; Sangeeta Nath^a ; ^{Sangeeta.Nath@liu.se" class="auth_mail}
• 关键词：Alzheimer's disease ; Amyloid-尾 oligomers ; Cell-to-cell transfer ; Prion-like propagation ; Intracellular accumulation
• 刊名：Neurobiology of Disease
• 出版年：May, 2014
• 年：2014
• 卷：65
• 期：Complete
• 页码：82-92
• 全文大小：1958 K

文摘

The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (A尾) residues 1-42 (oA尾_1-42) using our donor-acceptor 3-D co-culture model. We now show that different A尾-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific A尾-isoform. Although different A尾 isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining A尾 can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone A尾_1-42 isoform, which further promotes cell-to-cell transfer; thus, oA尾_1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.