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Human secreted tau increases amyloid-beta production
Open accessAbstract
The interaction of amyloid-beta (Aβ) and tau in the pathogenesis of Alzheimer's disease is a subject of intense inquiry, with the bulk of evidence indicating that changes in tau are downstream of Aβ. It has been shown however, that human tau overexpression in amyloid precursor protein transgenic mice increases Aβ plaque deposition. Here, we confirm that human tau increases Aβ levels. To determine if the observed changes in Aβ levels were because of intracellular or extracellular secreted tau (eTau for extracellular tau), we affinity purified secreted tau from Alzheimer's disease patient-derived cortical neuron conditioned media and analyzed it by liquid chromatography-mass spectrometry. We found the extracellular species to be composed predominantly of a series of N-terminal fragments of tau, with no evidence of C-terminal tau fragments. We characterized a subset of high affinity tau antibodies, each capable of engaging and neutralizing eTau. We found that neutralizing eTau reduces Aβ levels in vitro in primary human cortical neurons where exogenously adding eTau increases Aβ levels. In vivo, neutralizing human tau in 2 human tau transgenic models also reduced Aβ levels. We show that the human tau insert sequence is sufficient to cause the observed increase in Aβ levels. Our data furthermore suggest that neuronal hyperactivity may be the mechanism by which this regulation occurs. We show that neuronal hyperactivity regulates both eTau secretion and Aβ production. Electrophysiological analysis shows for the first time that secreted eTau causes neuronal hyperactivity. Its induction of hyperactivity may be the mechanism by which eTau regulates Aβ production. Together with previous findings, these data posit a novel connection between tau and Aβ, suggesting a dynamic mechanism of positive feed forward regulation. Aβ drives the disease pathway through tau, with eTau further increasing Aβ levels, perpetuating a destructive cycle.
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“The developers of BMS-986168 observed that neurons derived from stem cells of patients with familial AD secreted amino-terminal tau fragments, termed e-tau215.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [215]
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Metadata
- Authors
- Bright, J., Hussain, S., Dang, V., Wright, S., Cooper, B., Byun, T., Ramos, C., Singh, A., Parry, G., Stagliano, N., & Griswold-Prenner, I.
- Corresponding author
- Stagliano, Nancy
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 36
- Issue
- 2
- Pages
- 693-709
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2044321001
- Cited by
- 230
- References
- 41
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 11 · 2023: 17 · 2022: 16 · 2021: 26 · 2020: 31 · 2019: 30 · 2018: 43 · 2017: 12 · 2016: 17 · 2015: 9
- FWCI
- 8.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Aging (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- amyloid-beta production, Alzheimer's disease, neuronal hyperactivity, cortical neurons, amyloid precursor protein transgenic mice, positive feedback loop
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Cerebral Cortex, Chromatography, Liquid, Humans, Mice, Transgenic, Neurons, Mass Spectrometry, Amyloid beta-Peptides, tau Proteins
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