Spreading of neurodegenerative pathology via neuron-to-neuron transmission of β-amyloid

Sangeeta Nath, Lotta Agholme, Firoz Roshan Kurudenkandy, Björn Granseth, Jan Marcusson, Martin Hallbeck

Research output: Contribution to journalArticlepeer-review

177 Citations (Scopus)

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 ofβ-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 intracellularAβ 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.

Original languageEnglish
Pages (from-to)8767-8777
Number of pages11
JournalJournal of Neuroscience
Volume32
Issue number26
DOIs
Publication statusPublished - 27-06-2012

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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