Acute models of tau hyperphosphorylation

Abstract

Since Tau hyperphosphorylation in the central nervous system (CNS) plays a major role in many neurodegenerative diseases as Alzheimer's disease and tauopathies, acute cellular and in vivo models represent inevitable tools to screen potential promising drug candidates. Since hypothermia has been discussed as to trigger Tau hyperphosphorylation, we aimed to investigate Tau phosphorylation profiles parallel in cellular and murine systems under hypothermic conditions. Hypothermia was either induced via pentobarbital injection in wildtype mice or hypothermic incubation of SH-SY5Y or SH-SY5Y overexpressing the longest isoform of human Tau 441 carrying two well-characterized mutations (SH-Tau) cells. Subsequently, total Tau and its phosphorylated species were analyzed in brains and cellular lysates. Moreover, evaluations of pGSK3 beta and beta amyloid levels were performed. In vivo, hypothermia triggered hyperphosphorylation of various Tau sites such as Ser396, Ser262 and Thr181 most likely via enhanced GSK3beta activity. Total Tau levels remained unaltered, whereas amyloid beta levels were significantly increased. In vitro, hypothermia-induced effects on Tau hyperphosphorylation were more prominent in SH-Tau than in SH cells pointing towards the need of human mutated Tau to enlarge the therapeutic window. As in mice, total Tau levels stayed unaltered, whereas pSer396 and pSer262 Tau levels were significantly enhanced in SH and even more pronounced in SH-Tau cells under hypothermic conditions. LiCl, a known kinase inhibitor reversed the hypothermia-induced hyperphosphorylation. Hypothermia in wildtype mice and SH-Tau cells triggers hyperphosphorylation and mimics pathogenic events found in various neurodegenerative diseases. Thus both models are useful and acute models to study CNS drug mechanisms.