Publications

BibTex format

@article{Bengoa-Vergniory:2021:10.1186/s40478-020-01117-y,
author = {Bengoa-Vergniory, N and Velentza-Almpani, E and Silva, AM and Scott, C and Vargas-Caballero, M and Sastre, M and Wade-Martins, R and Alegre, Abarrategui J},
doi = {10.1186/s40478-020-01117-y},
journal = {Acta Neuropathologica Communications},
title = {Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer’s disease},
url = {http://dx.doi.org/10.1186/s40478-020-01117-y},
volume = {9},
year = {2021}
}

Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BackgroundMultimerization is a key process in prion-like disorders such as Alzheimer’s disease (AD), since it is a requirement for self-templating tau and beta-amyloid amyloidogenesis. AT8-immunohistochemistry for hyperphosphorylated tau is currently used for the diagnosis and staging of tau pathology. Given that tau–tau interactions can occur in the absence of hyperphosphorylation or other post-translational modifications (PTMs), the direct visualization of tau multimerization could uncover early pathological tau multimers.MethodsHere, we used bimolecular fluorescent complementation, rapamycin-dependent FKBP/FRB-tau interaction and transmission electron microscopy to prove the in vitro specificity of tau-proximity ligation assay (tau-PLA). We then analyzed MAPT KO and P301S transgenic mice, and human hippocampus and temporal isocortex of all Braak stages with tau-PLA and compared it with immunohistochemistry for the diagnostic antibody AT8, the early phosphorylation-dependent AT180, and the conformational-dependent antibody MC1. Finally, we performed proteinase-K treatment to infer the content of amyloidogenic beta-sheet fold.ResultsOur novel tau-proximity ligation assay (tau-PLA) directly visualized tau–tau interactions in situ, and exclusively recognized tau multimers but not monomers. It elicited no signal in MAPT KO mouse brains, but extensively labelled P301S transgenic mice and AD brain. Two groups of structures were detected, a previously unreported widespread small-sized diffuse pathology and large, neurofibrillary-like lesions. Tau-PLA-labelled diffuse pathology appeared from the earliest Braak stages, mostly unaccompanied by tangle-like tau-immunohistochemistry, being significantly more sensitive than any small-sized dot-/thread-like pathology labelled by AT180-, AT8- and MC1-immunohistochemistry in most regions quantified at stages 0-II. Tau-PLA-labelled diffuse pathology was extremely sensitive to Proteinase-K, in contrast to large les
AU  - Bengoa-Vergniory,N
AU  - Velentza-Almpani,E
AU  - Silva,AM
AU  - Scott,C
AU  - Vargas-Caballero,M
AU  - Sastre,M
AU  - Wade-Martins,R
AU  - Alegre,Abarrategui J
DO  - 10.1186/s40478-020-01117-y
PY  - 2021///
SN  - 2051-5960
TI  - Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer’s disease
T2  - Acta Neuropathologica Communications
UR  - http://dx.doi.org/10.1186/s40478-020-01117-y
UR  - http://hdl.handle.net/10044/1/86455
VL  - 9
ER  -

Download

DrJavierAlegre Abarrategui

Contact

Assistant

Location

Summary

Citation

BibTex format

RIS format (EndNote, RefMan)