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Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer’s disease

Lookup NU author(s): Professor David Brooks

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes cortical MAPT (tau) aggregation in familial and idiopathic Alzheimer’s disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. In the present study, we show that tau can accumulate spontaneously in transgenic APPswe/PS1ΔE9 mice, provided that ageing is taken into account. Tau pathology is abundant around Aβ deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the APPswe/PS1ΔE9 brain by 18 months of age. Age-dependent increases in argyrophilia correlated positively with binding levels of the paired helical filament (PHF) tracer [18F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Quantitative proteomics identified sequences of hyperphosphorylated and three-repeat tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Tissue from the frontal gyrus of human subjects was used to validate these findings, revealing primarily quantitative differences between the pathology observed in AD patient vs. transgenic mouse tissue. As physiological levels of endogenous, ‘wild-type’ tau aggregate secondarily to Aβ in APPswe/PS1ΔE9 mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.


Publication metadata

Author(s): Metaxas A, Thygesen C, Kempf SJ, Anzalone M, Vaitheeswaran R, Petersen S, Landau AM, Audrain H, Teeling J, Darvesh S, Brooks DJ, Larsen MR, Finsen B

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2019

Volume: 9

Online publication date: 31/10/2019

Acceptance date: 13/10/2019

Date deposited: 14/10/2019

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41598-019-52357-5

DOI: 10.1038/s41598-019-52357-5


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