Chronological changes in the expression of phosphorylated tau and 5­AMP­activated protein kinase in the brain of senescence­accelerated P8 mice.

Senescence-accelerated mouse prone 8 (SAMP8), a non­transgenic animal model used for researching sporadic Alzheimer's disease (AD), presents AD pathologies and overall dysregulation in brain energy metabolism, which is one of the early pathogenic characteristics of AD. In the present study, the authors examined chronological changes in the expression patterns of phosphorylated tau and of proteins related to energy metabolism to evaluate the association of tau phosphorylation and metabolism, using young­ (2­months­old), middle­ (5­months­old) and old­aged (10­months­old) SAMP8. The levels of phosphorylated 5'­AMP activated protein kinase at Thr172 (p­AMPK) and phosphorylated glycogen synthase kinase 3ß (p­GSK3ßS9) in the cortex of SAMP8 at 2 months were significantly higher than those in senescence­accelerated mouse resistant 1 (SAMR1). The differences were not detected at 5 and 10 months of age, which were concurrent with the changes in levels of phosphorylated tau at Ser396 (p­tauS396), but not with p­tauS262. The level of p­tauS262 was considerably higher in the cortex of middle­aged SAMP8 when compared with that of SAMR1 and sustained in old­aged SAMP8, but not in the young cortex. The levels of cortical sirtuin1 (Sirt1) and insulin receptor substrate 1 (IRS­1) expression of young SAMP8 were significantly lower, when compared with those in SAMR1. However, in the hippocampus of SAMP8, the patterns of chronological changes and levels of p­tau, p­AMPK, Sirt1 and IRS­1 relative to SAMR1 were different from those in the cortex. Taken together, the results suggested that regulation of tau phosphorylation via the AMPK­GSK3ß pathway concurrent with dysregulation of energy metabolism may precede the pathological tau hyperphosphorylation in the cortex of SAMP8, and that the regulation of AMPK­GSK3ß­mediated tau phosphorylation may be dependent on phosphor­epitope in tau or the region of brain.