Premium
Early‐onset axonal pathology in a novel P 301 S ‐ T au transgenic mouse model of frontotemporal lobar degeneration
Author(s) -
Eersel Janet,
Stevens Claire H.,
Przybyla Magdalena,
Gladbach Amadeus,
Stefanoska Kristie,
Chan Chesed KaiXin,
Ong WeiYi,
Hodges John R.,
Sutherland Greg T.,
Kril Jillian J.,
Abramowski Dorothee,
Staufenbiel Matthias,
Halliday Glenda M.,
Ittner Lars M.
Publication year - 2015
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12233
Subject(s) - genetically modified mouse , frontotemporal lobar degeneration , pathology , tau protein , neurofilament , immunohistochemistry , tauopathy , transgene , microglia , tau pathology , frontotemporal dementia , biology , alzheimer's disease , neuroscience , microbiology and biotechnology , neurodegeneration , medicine , dementia , immunology , disease , biochemistry , inflammation , gene
Aim Tau becomes hyperphosphorylated in A lzheimer's disease ( AD ) and frontotemporal lobar degeneration ( FTLD ‐tau), resulting in functional deficits of neurones, neurofibrillary tangle ( NFT ) formation and eventually dementia. Expression of mutant human tau in the brains of transgenic mice has produced different lines that recapitulate various aspects of FTLD ‐tau and AD . In this study, we characterized the novel P 301 S mutant tau transgenic mouse line, TAU 58/2. Methods Both young and aged TAU 58/2 mice underwent extensive motor testing, after which brain tissue was analysed with immunohistochemistry, silver staining, electron microscopy and Western blotting. Tissue from various FTLD subtypes and AD patients was also analysed for comparison. Results TAU 58/2 mice presented with early‐onset motor deficits, which became more pronounced with age. Throughout the brains of these mice, tau was progressively hyperphosphorylated resulting in increased NFT formation with age. In addition, frequent axonal swellings that stained intensively for neurofilament ( NF ) were present in young TAU 58/2 mice prior to NFT formation. Similar axonal pathology was also observed in human FTLD ‐tau and AD . Interestingly, activated microglia were found in close proximity to neurones harbouring transgenic tau, but were not associated with NF ‐positive axonal swellings. Conclusions In TAU 58/2 mice, early tau pathology induces functional deficits of neurones associated with NF pathology. This appears to be specific to tau, as similar changes are observed in FTLD ‐tau, but not in FTLD with TDP ‐43 inclusions. Therefore, TAU 58/2 mice recapitulate aspects of human FTLD ‐tau and AD pathology, and will become instrumental in studying disease mechanisms and therapeutics in the future.