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Cited by 179Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer’s Disease

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Pickett, Eleanor K., Herrmann, Abigail G., McQueen, Jamie, Abt, Kimberly, Dando, Owen, Tulloch, Jane, Jain, Pooja, Dunnett, Sophie +22 more·2019·Cell Reports
DOI 10.1016/j.celrep.2019.11.044PMC PMC6915767
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Abstract

A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aβ) peptide and pathological forms of the tau protein cooperate in causing disease phenotypes. Within a mouse tau-deficient background, we probed the molecular, cellular, and behavioral disruption triggered by the influence of wild-type human tau on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity behavioral phenotype and to cause downregulation of transcription of genes involved in synaptic function. In both our mouse model and human postmortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau reduction in the mice initiated after behavioral deficits emerge corrects behavioral deficits, reduces synaptic tau levels, and substantially reverses transcriptional perturbations, suggesting that lowering synaptic tau levels may be beneficial in AD.

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  • Prior studies showed that either co-expressing APP and MAPT genes or using prion-like seeding paradigms led to exacerbated Aβ and tau pathologies.

    “Previous studies have shown that either co-expressing APP and MAPT genes (3, 6, 23) or using prion-like seeding paradigms (4, 24, 25) led to exacerbated Aβ and tau pathologies.”

    From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [23]

    This source is relevant to the co-expression part of the sentence, not the separately cited seeding paradigms. Its Results (Figure 1 and accompanying text; page unavailable) report that APP/PS1+Tau mice had lower plaque burden than APP/PS1 mice and developed no detectable tau pathology, contrary to the claimed exacerbation of both pathologies. (LLM, conf=0.90)

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  • Synaptic dysfunction is a hallmark of AD and has been reported in both combined pathology mouse models and human AD brains.

    “Synaptic dysfunction is a hallmark of AD and has been reported in both combined pathology mouse models and human AD brains. 43 , 58 , 59”

    From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [59]

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Authors
Pickett, E. K., Herrmann, A. G., McQueen, J., Abt, K., Dando, O., Tulloch, J., Jain, P., Dunnett, S., Sohrabi, S., Fjeldstad, M. P., Calkin, W., Murison, L., Jackson, R. J., Tzioras, M., Stevenson, A., d’Orange, M., Hooley, M., Davies, C., Colom-Cadena, M., Anton-Fernandez, A., King, D., Oren, I., Rose, J., McKenzie, C.-A., Allison, E., Smith, C., Hardt, O., Henstridge, C. M., Hardingham, G. E., & Spires-Jones, T. L.
Affiliations
  • University of Edinburgh (GB)
  • UK Dementia Research Institute (GB)
  • Harvard University (US)
  • Simons Initiative for the Developing Brain (GB)
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2019-12
Volume
29
Issue
11
Pages
3592-3604.e5
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2019.11.044
PMC
PMC6915767
OpenAlex
W2995323110
Cited by
179
References
17
Citations by year
2026: 22 · 2025: 18 · 2024: 27 · 2023: 25 · 2022: 31 · 2021: 28 · 2020: 27 · 2013: 1
FWCI
14.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
Funders
  • Alzheimer’s Research UK
  • Medical Research Scotland
  • Horizon 2020 (681181)
  • Alzheimer's Society
  • UK Dementia Research Institute
  • Age UK
  • Horizon 2020 Framework Programme
  • European Research Council
  • University of Edinburgh
  • Biotechnology and Biological Sciences Research Council
  • Medical Research Council (MR/K026992/1)
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, amyloid-beta, tau protein, synaptic gene expression, behavioral deficits
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Animals, Female, Humans, Male, Spatial Behavior, Synapses, Amyloid beta-Peptides, tau Proteins, Microglia, Mice, Transcriptome

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