Repository logo
 

Mislocalization of neuronal tau in the absence of tangle pathology in phosphomutant tau knockin mice.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Gilley, Jonathan 
Ando, Kunie 
Seereeram, Anjan 
Rodríguez-Martín, Teresa 
Pooler, Amy M 

Abstract

Hyperphosphorylation and fibrillar aggregation of the microtubule-associated protein tau are key features of Alzheimer's disease and other tauopathies. To investigate the involvement of tau phosphorylation in the pathological process, we generated a pair of complementary phosphomutant tau knockin mouse lines. One exclusively expresses phosphomimetic tau with 18 glutamate substitutions at serine and/or threonine residues in the proline-rich and first microtubule-binding domains to model hyperphosphorylation, whereas its phosphodefective counterpart has matched alanine substitutions. Consistent with expected effects of genuine phosphorylation, association of the phosphomimetic tau with microtubules and neuronal membranes is severely disrupted in vivo, whereas the phosphodefective mutations have more limited or no effect. Surprisingly, however, age-related mislocalization of tau is evident in both lines, although redistribution appears more widespread and more pronounced in the phosphomimetic tau knockin. Despite these changes, we found no biochemical or immunohistological evidence of pathological tau aggregation in mice of either line up to at least 2 years of age. These findings raise important questions about the role of tau phosphorylation in driving pathology in human tauopathies.

Description

Keywords

Hyperphosphorylation, Knockin mouse, Phosphodefective, Phosphomimetic, Tau, Tauopathy, Animals, Humans, Mice, Mutant Strains, Neurons, Phosphorylation, Protein Aggregation, Pathological, Tauopathies, tau Proteins

Journal Title

Neurobiol Aging

Conference Name

Journal ISSN

0197-4580
1558-1497

Volume Title

39

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MR/N004582/1)