Aβ accelerates the spatiotemporal progression of tau pathology and augments tau amyloidosis in an Alzheimer mouse model
Open accessAbstract
Senile plaques formed by β-amyloid peptides (Aβ) and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau, a microtubule-associated protein, are the hallmark lesions of Alzheimer's disease (AD) in addition to loss of neurons. While several transgenic (Tg) mouse models have recapitulated aspects of AD-like Aβ and tau pathologies, a spatiotemporal mapping paradigm for progressive NFT accumulation is urgently needed to stage disease progression in AD mouse models. Braak and co-workers developed an effective and widely used NFT staging paradigm for human AD brains. The creation of a Braak-like spatiotemporal staging scheme for tau pathology in mouse models would facilitate mechanistic studies of AD-like tau pathology. Such a scheme would also enhance the reproducibility of preclinical AD therapeutic studies. Thus, we developed a novel murine model of Aβ and tau pathologies and devised a spatiotemporal scheme to stage the emergence and accumulation of NFTs with advancing age. Notably, the development of NFTs followed a spatiotemporal Braak-like pattern similar to that observed in authentic AD. More significantly, the presence of Aβ accelerated NFT formation and enhanced tau amyloidosis; however, tau pathology did not have the same effect on Aβ pathology. This novel NFT staging scheme provides new insights into the mechanisms of tau pathobiology, and we speculate that this scheme will prove useful for other basic and translational studies of AD mouse models.
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Using the same line of P301S tau transgenic mice, a trend towards a higher extracellular amyloid plaque load was detected in PDAPP/Tau bigenic mice.
“Using the same line of P301S tau transgenic mice, a trend towards a higher extracellular amyloid plaque load was detected in PDAPP/Tau bigenic mice [8], while no evidence for increased Aβ pathology was evident in 5XFAD/PS19 mice at either 3 or 9 months of age [9].”
From Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau (2021) · cites this paper as [8]
The Discussion states the opposite trend: bigenic PS19;PDAPP mice had fewer Aβ deposits, not a higher plaque load. Figure 6 likewise describes greater plaque burden in monogenic PDAPP mice. (LLM, conf=0.94)
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Experimental — accuracy not yet measuredFindings in models harboring transgenic Aβ peptides in the absence of APP overexpression strikingly contrast the obvious exacerbation of tau pathology observed in tau transgenic mice when crossed with mouse models of AD overexpressing mutant APP.
“These findings in models harboring transgenic Aβ peptides in the absence of APP overexpression strikingly contrast the obvious exacerbation of tau pathology observed in tau transgenic mice when crossed with mouse models of AD overexpressing mutant APP [7,8,9,10,11,12,13,36].”
From Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau (2021) · cites this paper as [8]
There is an insignificant reduction in Aβ burden and detergent-soluble Aβ oligomers in these mice, similar to a previous report showing reduction of Aβ plaques in bigenic PS19 x PDAPP mice.
“There is an insignificant reduction in Aβ burden and detergent-soluble Aβ oligomers in these mice, which is similar to a previous report showing reduction of Aβ plaques in a bigenic PS19 x PDAPP mice (35).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [35]
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- Authors
- Hurtado, D. E., Molina-Porcel, L., Iba, M., Aboagye, A. K., Paul, S. M., Trojanowski, J. Q., & Lee, V. M.-Y.
- Affiliations
- University of Pennsylvania (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Lee, Virginia M.-Y.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 177
- Issue
- 4
- Pages
- 1977-1988
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2947292
- OpenAlex
- W2117926331
- Cited by
- 222
- References
- 35
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 15 · 2023: 18 · 2022: 8 · 2021: 24 · 2020: 19 · 2019: 13 · 2018: 14 · 2017: 15 · 2016: 10 · 2015: 17 · 2014: 17 · 2013: 8 · 2012: 10
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG11542, T32-GM07229, T32-AG000255)
- 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 pathology, neurofibrillary tangles, Braak staging, transgenic mouse model, tau hyperphosphorylation
- MeSH terms
- Alzheimer Disease, Amyloidosis, Animals, Body Weight, Brain, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Humans, Immunoenzyme Techniques, Mice, Transgenic, Neurons, Phenotype, Survival Rate, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Disease Progression, Mice, Plaque, Amyloid
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