Phosphorylation of protein Tau by GSK3β prolongs survival of bigenic Tau.P301L × GSK3β mice by delaying brainstem tauopathy

• Main Authors: Natalia Crespo-Biel, Clara Theunis, Peter Borghgraef, Benoit Lechat, Herman Devijver, Hervé Maurin, Fred Van Leuven
• Format: Article
• Language: English
• Published: Elsevier 2014-07-01
• Series: Neurobiology of Disease
• Subjects: GSK3; Protein Tau; Tauopathy; Brainstem; Survival
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996114000771

Tau.P301L transgenic mice suffer precocious mortality between ages 8 and 11 months, resulting from upper airway defects caused by tauopathy in autonomic brainstem circuits that control breathing (Dutschmann et al., 2010). In individual mice, the clinical phenotype evolves progressively and rapidly (3–6 weeks) from clasping, over general motor impairment to severe reduction in body-weight into the terminal phase that announces imminent death (<3 days). Surprisingly, co-expression of GSK3β with Tau.P301L significantly prolonged survival of bigenic biGT mice (Terwel et al., 2008), which we here assign to delayed development of brainstem tauopathy. Eventually, brainstem tauopathy became as prominent in old biGT mice in the specified brainstem nuclei as in the parental Tau.P301L mice, resulting in similar clinical deterioration and terminal phase preceding death, although at later age. Biochemically, in both genotypes the pathway to neurofibrillary tangles and neuropil threads was similar: phosphorylation of protein Tau and formation of soluble oligomers and insoluble aggregates, ending in the typical tangles and threads of tauopathy. The extra GSK3β activity led to expected increased phosphorylation of protein Tau, particularly at residues S262 and S396, which we must conclude to delay the aggregation of protein Tau in the brainstem of aging biGT mice. The unexpected, paradoxical alleviation of the brainstem problems in biGT mice allowed them to grow older and thereby develop more severe tauopathy in forebrain than Tau.P301L mice, which succumb at younger age.