Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of -Amyloid
Open accessAbstract
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.
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Several studies have shown that both extracellular free Aβ and Aβ-contained EVs play a role in the progression of AD pathology.
“Several studies have shown that both extracellular free Aβ and Aβ-contained EVs play a role in the progression of AD pathology [136–140].”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [140]
The Introduction describes exogenous Aβ aggregates inducing pathology, and the Discussion reports that Aβ can be secreted in exosomes. But this study demonstrates transfer of intracellular Aβ through direct neuronal connections; it does not show that both free extracellular Aβ and Aβ-containing extracellular vesicles drive AD progression. The Discussion treats exosome trafficking as a possible mechanism, not an established one (page numbers unavailable in our copy). (LLM, conf=0.86)
Experimental — accuracy not yet measuredAmyloid pathology might be gradually transmitted through connected brain structures.
“Some studies have indicated that amyloid pathology might be gradually transmitted through connected brain structures [10, 69, 84, 96], by mechanisms that are still under investigation.”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [84]
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- Authors
- Nath, S., Agholme, L., Kurudenkandy, F. R., Granseth, B., Marcusson, J., & Hallbeck, M.
- Affiliations
- Linköping University (SE)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-06-27
- Volume
- 32
- Issue
- 26
- Pages
- 8767-8777
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6622335
- OpenAlex
- W2100421640
- Cited by
- 244
- References
- 50
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 14 · 2023: 11 · 2022: 15 · 2021: 16 · 2020: 17 · 2019: 17 · 2018: 19 · 2017: 17 · 2016: 28 · 2015: 13 · 2014: 25 · 2013: 27 · 2012: 5
- FWCI
- 15.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation pour la Recherche Médicale
- Vetenskapsrådet
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta oligomers, neurodegeneration, hippocampal neurons, amyloid plaques, disease progression, cognitive decline
- MeSH terms
- Animals, Animals, Newborn, Cell Communication, Cell Differentiation, Cells, Cultured, Dendrites, Dose-Response Relationship, Drug, Endocytosis, Exocytosis, Female, Heterocyclic Compounds, 3-Ring, Hippocampus, Humans, Male, Membrane Glycoproteins, Microinjections, Nerve Degeneration, Nerve Tissue Proteins, Synaptic Transmission, Neuroblastoma, Neuroglia, Neurons, Peptide Fragments, Rhodamines, Tetrazolium Salts, Thiazoles, Time Factors, Transfection, Amyloid beta-Peptides, Rats, Sprague-Dawley, Patch-Clamp Techniques, Coculture Techniques, Neocortex, rab5 GTP-Binding Proteins, Microscopy, Electron, Transmission, Green Fluorescent Proteins, Rats, Lysosomal-Associated Membrane Protein 2
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