Parallel increase in p70 kinase activation and tau phosphorylation (S262) with Aβ overproduction

Abstract

This study set out to search for a link between overproduction of Ab and p70S6 kinase (p70S6K) phosphorylation/ activation. Results showed that levels of p-p70S6K at T421/ S424 and T389 are significantly increased in mouse N2a neuroblastoma cells carrying human APP with Swedish mutation (APPswe), and in transgenic APPswe/PS1 (A246E) mice as compared with respective controls, corresponding to the increase of tau phosphorylation at S262. This parallel increase in p70S6K activation and tau phosphorylation could be demonstrated by treating wild-type N2a cells with Ab25-35. Our results suggest that the Ab deposition in senile plaques in Alzheimer disease brains might be a primary event that activates p70S6K and phosphorylates tau at S262, resulting in microtubule disruption.

The mammalian target of rapamycin at the crossroad between cognitive aging and Alzheimer’s disease

“…For example, mTOR is upregulated in chinese hamster ovary (CHO) cells and mouse neuroblastoma cells (N2A) stably transfected with mutant APP. 68,69 mTOR hyperactivity was also induced in wild-type N2A cells by application of Aβ 25–35 . 68 In mutant CHO cells, which are known to secrete low concentration of low molecular weight Aβ oligomers, 70 the effects on mTOR were prevented by blocking Aβ production.…”

“…68,69 mTOR hyperactivity was also induced in wild-type N2A cells by application of Aβ 25–35 . 68 In mutant CHO cells, which are known to secrete low concentration of low molecular weight Aβ oligomers, 70 the effects on mTOR were prevented by blocking Aβ production. 69 Consistent with these findings, intrahippocampal injection of naturally secreted Aβ oligomers was sufficient to increase mTOR signaling in the brains of wild-type mice.…”

“…To this end, it has been reported that 12-month-old APP/PS1 mice have lower mTOR signaling than age-matched wild-type mice, 12 which directly contradicts an earlier report showing hyperactive mTOR signaling in 9-month-old APP/PS1 mice. 68 In Tg2576 mice, mTOR signaling is downregulated in young pre-pathological mice. In contrast, in aged Tg2575 mice with established Aβ pathology, mTOR activity is similar to age-matched wild-type mice.…”

Functional Role of RNA Polymerase II and P70 S6 Kinase in KCl Withdrawal-induced Cerebellar Granule Neuron Apoptosis

“…Therefore, it is possible that the increased phosphorylation of P70S6K at Ser-411, Thr-421, and Ser-424, but not at the rapamycin-sensitive Thr-389 site, in neurons undergoing cell death is brought about by activation of Cdks. Activation of P70S6K has been implicated in increased translation of Tau mRNA and A␤-dependent Tau hyperphosphorylation and tangle formation in Alzheimer disease (65)(66)(67). Deletion of P70S6K has been shown to enhance learning and behavior and to increase life span and resistance to age-related pathologies in mice (68,69).…”

mTOR‐dependent signalling in Alzheimer's disease

“…A significant increase of p‐p70S6K at the T421/S424 and T389 sites was found in N2a cells carrying human APP with Swedish mutation (APPswe) and in the homogenates from the brain regions of transgenic APPswe/PS1 (A246E) mice where most SPs localize, as compared with respective controls. Levels of these phosphorylation sites of p70S6K correspond to the increase of tau phosphorylation at the S262 site [56]. This parallel increase in p70S6K activation and tau phosphorylation could be demonstrated by treating wild‐type N2a cells with Aβ25–35.…”