Specific tau phosphorylation sites in hippocampus correlate with impairment of step-down inhibitory avoidance task in rats

Microtubule associated protein tau is abnormally phosphorylated in Alzheimer's disease (AD) and aggregates as paired helical filaments (PHFs) in neurofibrillary tangles (NFTs), which are one of the pathological signatures of AD and their presence correlates with severity of dementia. Dysfunction of protein phosphatases in the effected neurons is proposed to be a possible causative factor to AD development. We show here that the pattern of tau phosphorylation correlates with the decline of memory retention ability in rat brain. In our study, we have chosen 55 rats of full age to conduct the discrimination between their normal and low ability of memory retention in one-trial step-down test. It was found that among rats that developed the impairment in memory retention in step-down inhibitory avoidance task, tau protein in their hippocampus was hyperphosohorylated at Thr231/Ser235 (M4) sites of tau, and the significantly increased expression of PP-1 and the decreased one of PP-2B were also determined by Western blot and/or immunohistochemistry. It is implicated that: (1) the hyperphosphorylation of tau at M4 sites may be crucial to affect the memory retention of elder rats; (2) PP-1 might participate in the regulation of phosphorylation at Thr231 and Ser235 epitope of tau in vivo, and the up-regulation of PP-1 content could be in relation to tau hyperphosphorylation at Thr231/Ser235 sites of brain tau and the worse memory retention of rats indirectly; and (3) the decline of PP-2B content could induced the hyperphosphorylation of tau at M4 sides in vivo. (C) 2004 Elsevier B.V. All rights reserved.