title: Spreading of neurodegenerative pathology via neuron-to-neuron transmission of β-amyloid.
abstract: Alzheimer's disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of β-amyloid (Aβ) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble Aβ oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric Aβ. Additional studies conducted in a human donor-acceptor cell model show that this Aβ transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular Aβ oligomers play a role in neurodegeneration, and they explain the manner in which Aβ can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.
authors: Divisions of Geriatrics, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 83 Linköping, Sweden.
authors: Sangeeta
authors: S
authors: Nath
authors: Lotta
authors: L
authors: Agholme
authors: Firoz Roshan
authors: FR
authors: Kurudenkandy
authors: Björn
authors: B
authors: Granseth
authors: Jan
authors: J
authors: Marcusson
authors: Martin
authors: M
authors: Hallbeck
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003712:Dendrites / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008845:Microinjections; D046529:Microscopy, Electron, Transmission; D019579:Neocortex / Q000166:cytology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012235:Rhodamines; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014162:Transfection; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006575:Heterocyclic Compounds, 3-Ring; D052119:Lysosomal-Associated Membrane Protein 2; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D012235:Rhodamines; C489618:Sv2a protein, rat; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C485184:enhanced green fluorescent protein; C412715:tetramethylrosamine; D049452:Green Fluorescent Proteins; D020696:rab5 GTP-Binding Proteins; C022616:thiazolyl blue