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

Jakob Domert, Sahana Bhima Rao, Lotta Agholme, Ann Christin Brorsson, Jan Marcusson, Martin Hallbeck, Sangeeta Nath

Research output: Contribution to journalArticlepeer-review

102 Citations (Scopus)

Abstract

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 (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-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 Aβ-isoform. Although different Aβ 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 Aβ 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 Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 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.

Original languageEnglish
Pages (from-to)82-92
Number of pages11
JournalNeurobiology of Disease
Volume65
DOIs
Publication statusPublished - 05-2014

All Science Journal Classification (ASJC) codes

  • Neurology

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