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O4‐04‐02: Identification of proteins that form complexes with tau in mouse brain
Author(s) -
Moechars Diederik,
Winderickx Joris,
Fischer Frank,
Jundt Melanie,
Mercken Marc,
Bantscheff Marcus,
Rowley Adele,
Van Leuven Fred,
Karran Eric,
Drewes Gerard,
Joberty Gerard
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.482
Subject(s) - tau protein , neurodegeneration , microtubule , protein–protein interaction , tauopathy , biology , corticobasal degeneration , chemistry , biochemistry , alzheimer's disease , microbiology and biotechnology , progressive supranuclear palsy , disease , medicine , pathology , genetics , atrophy
Pin1 knockout in mice causes both tau and Ab-related pathologies as well as neurodegeneration in an age-dependent manner. By contrast, transgenic Pin1 overexpression in postnatal neurons prevents the development of AD in mice. Together with the findings that Pin1 is inhibited by multiple mechanisms in human AD, these results indicate that Pin1 is pivotal for protecting against AD. However, it is not clear how Pin1 protects against tau and Abeta-related pathologies and whether Pin1 affects onset of AD. Methods: We have used multiple approaches, including generating conformation-specific antibodies, using NMR, cell cultures, mouse models, human samples and genetic association studies. Results: We found that Pin1 promoted cis to trans isomerization of the pThr231-Pro motif in tau and pThr668-Pro motif in APP. Without functional Pin1, both tau and APP were accumulated in the cis conformation, which led to increased tau phosphorylation and reduced tau degradation, as well as increased APP internalization, resulting in amyloidogenic APP processing and Abeta production. The significance of these findings is further substantiated by our identification of a functional polymorphism in the Pin1 promoter that was significantly associated with a 3-year delay in the average age-at-onset (AAO) of late-onset AD in a Chinese population. This Pin1 polymorphism completely abolished the ability of a brain-selective transcription factor to bind and suppress the Pin1 promoter and to reduce Pin1 protein levels. Conclusions: We have shown that Pin1 is a pivotal new enzyme that protects against tau and Abeta-related pathologies in AD by controlling the conformation of tau and APP after phosphorylation and also identify a novel Pin1 regulation that is critical in determining onset of AD. These results further demonstrate that Pin1 is an attractive novel therapeutic target to treating AD or delay its onset.