Tau Ser262 phosphorylation is critical for A 42-induced tau toxicity in a transgenic Drosophila model of Alzheimer's disease
Open accessAbstract
The amyloid-beta 42 (Abeta42) peptide has been suggested to promote tau phosphorylation and toxicity in Alzheimer's disease (AD) pathogenesis; however, the underlying mechanisms are not fully understood. Using transgenic Drosophila expressing both human Abeta42 and tau, we show here that tau phosphorylation at Ser262 plays a critical role in Abeta42-induced tau toxicity. Co-expression of Abeta42 increased tau phosphorylation at AD-related sites including Ser262, and enhanced tau-induced neurodegeneration. In contrast, formation of either sarkosyl-insoluble tau or paired helical filaments was not induced by Abeta42. Co-expression of Abeta42 and tau carrying the non-phosphorylatable Ser262Ala mutation did not cause neurodegeneration, suggesting that the Ser262 phosphorylation site is required for the pathogenic interaction between Abeta42 and tau. We have recently reported that the DNA damage-activated Checkpoint kinase 2 (Chk2) phosphorylates tau at Ser262 and enhances tau toxicity in a transgenic Drosophila model. We detected that expression of Chk2, as well as a number of genes involved in DNA repair pathways, was increased in the Abeta42 fly brains. The induction of a DNA repair response is protective against Abeta42 toxicity, since blocking the function of the tumor suppressor p53, a key transcription factor for the induction of DNA repair genes, in neurons exacerbated Abeta42-induced neuronal dysfunction. Our results demonstrate that tau phosphorylation at Ser262 is crucial for Abeta42-induced tau toxicity in vivo, and suggest a new model of AD progression in which activation of DNA repair pathways is protective against Abeta42 toxicity but may trigger tau phosphorylation and toxicity in AD pathogenesis.
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Studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity depends on tau phosphorylation at these sites.
“Notably, studies in cultured neurons and transgenic Drosophila showed that Aβ-induced augmentation of tau toxicity caused by Aβ depends on tau phosphorylation at these sites [39, 45, 56–58].”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [58]
The Results and Discussion report that the non-phosphorylatable Ser262Ala mutation prevented Aβ42-associated neurodegeneration in transgenic Drosophila. The paper does not establish the same dependence in cultured neurons, or show that phosphorylation at the other sites measured is required for the effect. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFormation of fibrils or detergent-insoluble aggregates are not detected in the presence or absence of Aβ in Drosophila models.
“Formation of fibrils or detergent-insoluble aggregates are not detected in the presence or absence of Aβ [58, 59]”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [58]
The Introduction (page unavailable) says neurofibrillary tangles are not observed in fly neurons. Figure 2D (page unavailable) reports that Aβ42 co-expression did not increase sarkosyl-insoluble tau, but it does not say detergent-insoluble tau was undetectable in either condition. The claim of no detectable fibrils or insoluble aggregates with or without Aβ is therefore stronger than the cited evidence. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSubstitution of two Ser residues at 262 and 356 in tau to unphosphorylatable Ala (S2A) suppressed Aβ42-induced augmentation of tau toxicity.
“Previous studies from several groups, including ours, showed that substitution of two Ser residues at 262 and 356 in tau to unphosphorylatable Ala (S2A) suppressed Aβ42-induced augmentation of tau toxicity ([58] and Fig 3A).”
From Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity (2016) · cites this paper as [58]
The results section (Fig. 3B–F; page unavailable) reports that co-expressing Aβ42 with tau carrying the single S262A mutation did not cause the observed eye or brain defects, supporting the role of Ser262 in Aβ42-induced tau toxicity. It does not report that the double S262A/S356A mutant (S2A) suppressed that effect; the discussion mentions that double mutant in relation to a different form of tau toxicity. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAβ42-mediated augmentation of tau toxicity is not simply due to an overall increase in the level of tau.
“suggesting that Aβ42-mediated augmentation of tau toxicity is not simply due to an overall increase in the level of tau [58].”
Aβ42 co-expression enhances tau-mediated retinal degeneration in fly eyes.
“As reported previously, co-expression of Aβ42 in fly eyes using the pan-retinal driver gmr-Gal4 enhanced tau-mediated retinal degeneration ([58] and S1 Fig).”
Aβ42 increased levels of tau phosphorylated at Ser202 and Thr231.
“As we reported previously, Aβ42 increased the levels of tau phosphorylated at Ser202 (pSer202) and Thr231 (pThr231) ([58] and Fig 2B).”
Aβ42 increases the level of tau phosphorylated at Ser262 in the fly retina.
“The level of tau phosphorylated at Ser262 is elevated in the Aβ42 fly retina [58] (Fig 5A)”
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- Authors
- Iijima, K., Gatt, A., & Iijima-Ando, K.
- Affiliations
- Thomas Jefferson University (US)
- Corresponding author
- Iijima, K.
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-05-12
- Volume
- 19
- Issue
- 15
- Pages
- 2947-2957
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2901137
- OpenAlex
- W2142964430
- Cited by
- 96
- References
- 16
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 9 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 3 · 2018: 2 · 2017: 8 · 2016: 6 · 2015: 6 · 2014: 6 · 2013: 10 · 2012: 5
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association (NIRG-08-91985)
- Thomas Jefferson University
- National Institutes of Health
- National Institute on Aging (R01AG032279)
- 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 › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- tau phosphorylation, amyloid-beta 42, tau toxicity, Alzheimer's disease, transgenic Drosophila, Chk2, DNA repair, p53, neurodegeneration, paired helical filaments, sarkosyl-insoluble tau
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, DNA Repair, Drosophila melanogaster, Eye, Humans, Motor Activity, Nerve Degeneration, Peptide Fragments, Phosphorylation, Phosphoserine, Signal Transduction, Amyloid beta-Peptides, tau Proteins, Protein Serine-Threonine Kinases, Animals, Genetically Modified, Checkpoint Kinase 2
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