Background: Intracellular accumulation of tau as neurofibrillary tangles (NFTs) is the hallmark of Alzheimer's disease (AD) as well as in other tauopathies. Tau is present not only in the cytoplasm but also in the extracellular space such as cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Although clearance is one critical parameter leading to such intracellular/extracellular tau accumulation, in vivo turnover of tau has not been well characterized. The current study has attempted to precisely determine in vivo turnover rates of tau utilizing tet-off regulatable mice. In particular, we assessed intracellular tau and extracellular tau, soluble tau, insoluble tau and phosphorylated tau at certain sites utilizing a combination of in vivo microdialysis, biochemical analysis and specific ELISAs recognizing each species. To examine the effect of a tauopathy-associated mutation on tau clearance, half-lives of various tau species were compared between the mice with a FTDP-17 mutation that induces β-sheet formation, ΔK280 mutation (pro-aggregant mice) and control mice with additional β-sheet breaking mutations (anti-aggregant mice).
Results: Here we report that tau is metabolized at much slower turnover rates in vivo than in cell culture. We found that insoluble tau in pro-aggregant mice had a significantly slower half-life (t1/2 = ~34.2 days) than soluble tau (t1/2 = ~9.7 days). In contrast, soluble tau phosphorylated in the proline rich region was cleared faster than total soluble tau. When comparing pro-aggregant mice to anti-agregant mice, turnover rates of soluble tau species were not significantly different.
Conclusions: The current study provides a comprehensive description of in vivo turnover of various tau species present in mice that express human tau. The turnover rate of soluble tau was not significantly altered between pro-aggregant mice and anti-aggregant mice. This suggests that altered conformation by ΔK280 does not have a major impact on clearance pathways for soluble tau. In contrast, different tau species displayed different half-lives. Turnover was significantly delayed for insoluble tau whereas it was accelerated for soluble tau phosphorylated in the proline rich region. These differences in susceptibilities to clearance suggest that aggregation and phosphorylation influences tau clearance which may be important in tau pathogenesis.