title: Spreading of amyloid-β peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance.
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.
authors.affiliation: Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Domert
authors.affiliation: Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping, Sweden.
authors.forename: Sahana Bhima
authors.initials: SB
authors.lastname: Rao
authors.affiliation: Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Agholme
authors.affiliation: Department of Physics, Chemistry and Biology, IFM, Linköping University, Linköping, Sweden.
authors.forename: Ann-Christin
authors.initials: AC
authors.lastname: Brorsson
authors.affiliation: Division of Geriatric Medicine, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Marcusson
authors.affiliation: Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping, Sweden; Department of Clinical Pathology, County Council of Östergötland, Linköping, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Hallbeck
authors.affiliation: Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping, Sweden. Electronic address: Sangeeta.Nath@liu.se.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Nath
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002450:Cell Communication / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D005109:Extracellular Matrix / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020932:Nerve Growth Factor / Q000494:pharmacology; D020890:Neuregulin-1 / Q000494:pharmacology; D016501:Neurites / Q000378:metabolism* / Q000648:ultrastructure; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism* / Q000648:ultrastructure; D020033:Protein Isoforms; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D020890:Neuregulin-1; D010446:Peptide Fragments; D020033:Protein Isoforms; C485184:enhanced green fluorescent protein; C117467:neuregulin beta; D049452:Green Fluorescent Proteins; D014212:Tretinoin; D020932:Nerve Growth Factor
keywords: Alzheimer's disease; Amyloid-β oligomers; Cell-to-cell transfer; Intracellular accumulation; Prion-like propagation