The neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model
Open accessAbstract
A central question in Alzheimer’s Disease (AD) is whether the neuritic plaque is necessary and sufficient for the development of tau pathology. Hyperphosphorylation of tau is found within dystrophic neurites surrounding β-amyloid deposits in AD mouse models but the pathological conversion of tau is absent. Likewise, expression of a human tau repeat domain in mice is insufficient to drive the pathological conversion of tau. Here we developed an Aβ-amyloidosis mouse model that expresses the human tau repeat domain and show that in these mice, the neuritic plaque facilitates the pathological conversion of wild-type tau. We show that this tau fragment seeds the neuritic plaque-dependent pathological conversion of wild-type tau that spreads from the cortex and hippocampus to the brain stem. These results establish that in addition to the neuritic plaque, a second determinant is required to drive the conversion of wild-type tau.
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Phosphorylation of tau within dystrophic neurites subsequently contributes to the formation of neuritic plaques during AD progression.
“In the context of AD or aging, the formation of filamentous plaques has been associated with the phosphorylation of tau within dystrophic neuritis [13, 53, 106], which subsequently contributes to the formation of neuritic plaques (a subset of Aβ plaques surrounded by and containing dystrophic neurites) during AD progression”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [53]
The Results section (‘Neuritic plaque is not sufficient for the conversion of tau’) reports that tau was not hyperphosphorylated before neuritic plaques formed. Although the paper confirms phosphorylated tau within dystrophic neurites around plaques, its Discussion proposes the opposite sequence: Aβ-dependent plaque formation provides the environment for tau modification, not that tau phosphorylation subsequently forms the plaques. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe microenvironment in Aβ plaques plays a crucial role in Aβ-mediated neuroinflammation and tau pathogenesis in AD mouse models.
“Moreover, the microenvironment in Aβ plaques plays a crucial role in Aβ-mediated neuroinflammation and tau pathogenesis in AD mouse models [34, 53, 106].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [53]
The Results and Discussion (pages unavailable) show that neuritic plaques facilitate tau phosphorylation and are required, but not sufficient, for pathological tau conversion in the mouse model. The paper notes that astrocytes and microglia surround plaques, but the passages do not establish a crucial role for the plaque microenvironment in Aβ-mediated neuroinflammation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the context of AD or aging, the formation of filamentous plaques has been associated with the phosphorylation of tau within dystrophic neurites.
“In the context of AD or aging, the formation of filamentous plaques has been associated with the phosphorylation of tau within dystrophic neuritis [13, 53, 106], which subsequently contributes to the formation of neuritic plaques (a subset of Aβ plaques surrounded by and containing dystrophic neurites) during AD progression”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [53]
The Results section (‘Neuritic plaque is not sufficient for the conversion of tau’; page unavailable) reports that neuritic plaques in aging AD-model mice were associated with tau hyperphosphorylation within dystrophic neurites, and that phosphorylation was not observed before plaque formation. It does not identify these as ‘filamentous plaques’ or establish the association across AD or aging generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAβ plaques create a unique environment that triggers tau phosphorylation within dystrophic neuritis in a mouse model of amyloidosis.
“In a mouse model of amyloidosis, it has been observed that Aβ plaques create a unique environment that triggers tau phosphorylation within dystrophic neuritis [53].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [53]
Overexpression of a seed-competent tau fragment can induce the pathological conversion of WT mouse tau in mice with neuritic Aβ plaques.
“though overexpression of a seed-competent tau fragment can induce the pathological conversion of WT mouse tau in mice with neuritic Aβ plaques (8).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [8]
An earlier report showed that presence of seed-competent tau fragment is a major determinant required to trigger pathological conversion of soluble WT mouse tau into misfolded aggregates in the presence of neuritic plaques.
“This idea is consistent with an earlier report which showed that presence of seed-competent tau fragment is a major determinant required to trigger pathological conversion of soluble WT mouse tau into misfolded aggregates in the presence of neuritic plaques (8).”
From Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation (2022) · cites this paper as [8]
Tail biopsy samples were used to isolate DNA to confirm the genotype of the strain using previously established primers by PCR.
“Tail biopsy samples were used to isolate DNA to confirm the genotype of the strain using previously established primers by PCR93–95.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [93]
The Methods section on generation of transgenic mice describes the mouse lines and their crossbreeding, but does not describe how their genotypes were confirmed. Searches for tail-biopsy DNA, PCR genotyping, and primers found no passage establishing the procedure attributed to this paper; page numbers were unavailable in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured
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- Authors
- Li, T., Braunstein, K. E., Zhang, J., Lau, A., Sibener, L., Deeble, C., & Wong, P. C.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Li, Tong
- Venue
- Nature Communications
- Published
- 2016-07-04
- Volume
- 7
- Issue
- 1
- Pages
- 12082-12082
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4932197
- OpenAlex
- W2463705715
- Cited by
- 114
- References
- 71
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 28 · 2023: 6 · 2022: 10 · 2021: 9 · 2020: 15 · 2019: 7 · 2018: 10 · 2017: 6 · 2016: 3
- FWCI
- 6.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ellison Medical Foundation
- Johns Hopkins University
- National Institutes of Health
- National Institute on Aging (P50AG005146)
- 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 pathology, tau hyperphosphorylation, amyloid-beta, tau repeat domain, seeding, prion-like spread, dystrophic neurites, hippocampus, brainstem
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Gliosis, Humans, Male, Mice, Transgenic, Models, Biological, Phosphorylation, Neurites, Prosencephalon, tau Proteins, Repetitive Sequences, Amino Acid, Mutant Proteins, Plaque, Amyloid
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