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Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation.
Neuropathol Appl Neurobiol. 2022 02; 48(2):e12779.NA

Abstract

AIMS

To illuminate the pathological synergy between Aβ and tau leading to emergence of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), here, we have performed a comparative neuropathological study utilising three distinctive variants of human tau (WT tau, P301L mutant tau and S320F mutant tau). Previously, in non-transgenic mice, we showed that WT tau or P301L tau does not form NFT while S320F tau can spontaneously aggregate into NFT, allowing us to test the selective vulnerability of these different tau conformations to the presence of Aβ plaques.

METHODS

We injected recombinant AAV-tau constructs into neonatal APP transgenic TgCRND8 mice or into 3-month-old TgCRND8 mice; both cohorts were aged 3 months post injection. This allowed us to test how different tau variants synergise with soluble forms of Aβ (pre-deposit cohort) or with frank Aβ deposits (post-deposit cohort).

RESULTS

Expression of WT tau did not produce NFT or altered Aβ in either cohort. In the pre-deposit cohort, S320F tau induced Aβ plaque deposition, neuroinflammation and synaptic abnormalities, suggesting that early tau tangles affect the amyloid cascade. In the post-deposit cohort, contemporaneous expression of S320F tau did not exacerbate amyloid pathology, showing a dichotomy in Aβ-tau synergy based on the nature of Aβ. P301L tau produced NFT-type inclusions in the post-deposit cohort, but not in the pre-deposit cohort, indicating pathological synergy with pre-existing Aβ deposits.

CONCLUSIONS

Our data show that different tau mutations representing specific folding variants of tau synergise with Aβ to different extents, depending on the presence of cerebral deposits.

Links

Authors+Show Affiliations

Department of Neuroscience, University of Florida, Gainesville, Florida, USA. Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA. Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA.

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA.

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA. Department of Neurology, University of Florida, Gainesville, Florida, USA.

Gonzalez De La Cruz E

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA.

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA.

Department of Neuroscience, University of Florida, Gainesville, Florida, USA. Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA.

Department of Neuroscience, University of Florida, Gainesville, Florida, USA. Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA.

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA.

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA.

Department of Neuroscience, University of Florida, Gainesville, Florida, USA. Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA. McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.

Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA. McKnight Brain Institute, University of Florida, Gainesville, Florida, USA. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, USA.

Department of Neuroscience, University of Florida, Gainesville, Florida, USA. Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, Florida, USA. McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.

MeSH

Alzheimer DiseaseAmyloid beta-PeptidesAnimalsBrainDisease Models, AnimalMiceMice, TransgenicNeurofibrillary TanglesNeuronsPlaque, Amyloidtau Proteins

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

Language

eng

PubMed ID

34825397

Citation

Koller, Emily J., et al. "Combinatorial Model of Amyloid Β and Tau Reveals Synergy Between Amyloid Deposits and Tangle Formation." Neuropathology and Applied Neurobiology, vol. 48, no. 2, 2022, pp. e12779.

Koller EJ, Ibanez KR, Vo Q, et al. Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation. Neuropathol Appl Neurobiol. 2022;48(2):e12779.

Koller, E. J., Ibanez, K. R., Vo, Q., McFarland, K. N., Gonzalez De La Cruz, E., Zobel, L., Williams, T., Xu, G., Ryu, D., Patel, P., Giasson, B. I., Prokop, S., & Chakrabarty, P. (2022). Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation. Neuropathology and Applied Neurobiology, 48(2), e12779. https://doi.org/10.1111/nan.12779

Koller EJ, et al. Combinatorial Model of Amyloid Β and Tau Reveals Synergy Between Amyloid Deposits and Tangle Formation. Neuropathol Appl Neurobiol. 2022;48(2):e12779. PubMed PMID: 34825397.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Combinatorial model of amyloid β and tau reveals synergy between amyloid deposits and tangle formation. AU - Koller,Emily J, AU - Ibanez,Kristen R, AU - Vo,Quan, AU - McFarland,Karen N, AU - Gonzalez De La Cruz,Elsa, AU - Zobel,Lillian, AU - Williams,Tristan, AU - Xu,Guilian, AU - Ryu,Daniel, AU - Patel,Preya, AU - Giasson,Benoit I, AU - Prokop,Stefan, AU - Chakrabarty,Paramita, Y1 - 2021/12/10/ PY - 2021/03/25/received PY - 2021/11/13/accepted PY - 2021/11/27/pubmed PY - 2022/4/1/medline PY - 2021/11/26/entrez KW - Alzheimer's disease KW - gliosis KW - neurofibrillary tangle KW - neuroinflammation KW - pathological synergy KW - plaque burden SP - e12779 EP - e12779 JF - Neuropathology and applied neurobiology JO - Neuropathol Appl Neurobiol VL - 48 IS - 2 N2 - AIMS: To illuminate the pathological synergy between Aβ and tau leading to emergence of neurofibrillary tangles (NFT) in Alzheimer's disease (AD), here, we have performed a comparative neuropathological study utilising three distinctive variants of human tau (WT tau, P301L mutant tau and S320F mutant tau). Previously, in non-transgenic mice, we showed that WT tau or P301L tau does not form NFT while S320F tau can spontaneously aggregate into NFT, allowing us to test the selective vulnerability of these different tau conformations to the presence of Aβ plaques. METHODS: We injected recombinant AAV-tau constructs into neonatal APP transgenic TgCRND8 mice or into 3-month-old TgCRND8 mice; both cohorts were aged 3 months post injection. This allowed us to test how different tau variants synergise with soluble forms of Aβ (pre-deposit cohort) or with frank Aβ deposits (post-deposit cohort). RESULTS: Expression of WT tau did not produce NFT or altered Aβ in either cohort. In the pre-deposit cohort, S320F tau induced Aβ plaque deposition, neuroinflammation and synaptic abnormalities, suggesting that early tau tangles affect the amyloid cascade. In the post-deposit cohort, contemporaneous expression of S320F tau did not exacerbate amyloid pathology, showing a dichotomy in Aβ-tau synergy based on the nature of Aβ. P301L tau produced NFT-type inclusions in the post-deposit cohort, but not in the pre-deposit cohort, indicating pathological synergy with pre-existing Aβ deposits. CONCLUSIONS: Our data show that different tau mutations representing specific folding variants of tau synergise with Aβ to different extents, depending on the presence of cerebral deposits. SN - 1365-2990 UR - https://www.unboundmedicine.com/medline/citation/34825397/Combinatorial_model_of_amyloid_β_and_tau_reveals_synergy_between_amyloid_deposits_and_tangle_formation_ DB - PRIME DP - Unbound Medicine ER -