Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration
Open accessAbstract
Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.
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Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis that lies upstream of tau-induced neurodegeneration.
“Genetic, pathological, and biochemical evidence suggests that elevation of Aβ levels is a causal event in AD pathogenesis [2–8] that lies upstream of tau-induced neurodegeneration [3, 5, 9, 10].”
Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD.
“Aβ promotes tau phosphorylation at disease-associated sites in in vitro and in vivo models of AD [2, 35–41].”
In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK.
“In cellular and animal models, co-expression of Aβ augments tau phosphorylation at these sites and increases the levels of active GSK3 and PAR-1/MARK [2, 35–41, 43, 44].”
Aggregated Aβ peptides may induce tau hyperphosphorylation both in vitro and in vivo.
“aggregated Aβ peptides may induce tau hyperphosphorylation both in vitro and in vivo (6, 26)”
From Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive tau PET in Alzheimer's disease (2020) · cites this paper as [6]
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“…AD, the density of hyperphosphorylated tau tangles is closely associated with β -amyloid. β -amyloid induces the hyperphosphorylation of tau in neurons and causes neurofibrillary deposition [34], and β -amyloid oligomers can cause tau protein hyperphosphorylation, leading to cognitive decline [35].”
BackgroundNeutralization of Soluble, Synaptotoxic Amyloid β Species by Antibodies Is Epitope Specific
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BackgroundHMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24
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- Authors
- Jin, M., Shepardson, N., Yang, T., Chen, G., Walsh, D., & Selkoe, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-03-18
- Volume
- 108
- Issue
- 14
- Pages
- 5819-5824
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3078381
- OpenAlex
- W2140323904
- Cited by
- 876
- References
- 46
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 44 · 2023: 46 · 2022: 47 · 2021: 63 · 2020: 69 · 2019: 62 · 2018: 62 · 2017: 66 · 2016: 59 · 2015: 63 · 2014: 73 · 2013: 66 · 2012: 76
- FWCI
- 54.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG 027443, AG006173)
- National Institute on Aging (AG027443, R01AG027443, R37AG006173, RF1AG006173, AG006173, R01AG006173)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, tau hyperphosphorylation, neurite degeneration, microtubule disruption, hippocampal neurons, neurofibrillary tangles, passive immunotherapy, tau antibodies, cortical amyloid
- MeSH terms
- Alzheimer Disease, Animals, Chromatography, Gel, Genetic Vectors, Hippocampus, Humans, Immunohistochemistry, Microtubules, Phosphorylation, Blotting, Western, Lentivirus, Amyloid beta-Peptides, Neurites, tau Proteins, Rats, Sprague-Dawley, Microscopy, Confocal, Dimerization, In Situ Nick-End Labeling, Immunoprecipitation, Rats
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