MECHANISMS OF OXIDATIVE SIGNALING TO AD NEUROPATHY

$269,836P01FY2012AGNIH

University Of North Texas Hlth Sci Ctr, Fort Worth TX

Investigators

Linked publications & trials

Paper 33436007 Paper 30594729 Paper 30365981 Paper 30090652 Paper 29730765 Paper 29477040 Paper 29152617 Paper 28652929 Paper 28463416 Paper 27939444 Paper 27888283 Paper 27818250 Paper 27714297 Paper 27317847 Paper 27235866 Paper 27221132 Paper 27220334 Paper 27114061 Paper 27092594 Paper 27004851 Paper 26990062 Paper 26891883 Paper 26827673 Paper 26740397 Paper 26473740 Paper 26463864 Paper 26208839 Paper 26144667 Paper 26140712 Paper 26088865 Paper 26082377 Paper 26052469 Paper 26048476 Paper 26023301 Paper 25964165 Paper 25681780 Paper 25646163 Paper 25542980 Paper 25542978 Paper 25492727 Paper 25204494 Paper 25149567 Paper 25104136 Paper 25015774 Paper 24941891 Paper 24905603 Paper 24780768 Paper 24558037 Paper 24496073 Paper 24473138 Paper 24434111 Paper 24424441 Paper 24380024 Paper 24279196 Paper 24219919 Paper 24065876 Paper 24029002 Paper 23976843 Paper 23959938 Paper 23845275 Paper 23726132 Paper 23662248 Paper 23643456 Paper 23437435 Paper 23415935 Paper 23340161 Paper 23205777 Paper 23173072 Paper 23139597 Paper 23138632 Paper 23088310 Paper 23054826 Paper 23036620 Paper 22778217 Paper 22732134 Paper 22538356 Paper 22509330 Paper 22498694 Paper 22435710 Paper 22285434 Paper 22155264 Paper 21968036 Paper 21907204 Paper 21647938 Paper 21573043 Paper 21540287 Paper 21508103 Paper 21454572 Paper 21296126 Paper 21262203 Paper 21237726 Paper 21111714 Paper 21075175 Paper 20842066 Paper 20828397 Paper 20807517 Paper 20732835 Paper 20714818 Paper 20691769 Paper 20457142

Abstract

During the course of this first funding cycle, Project 2 made several important discoveries. Among these were the following: (1) Multiple signaling kinases are persistently activated by pro-oxidant insults in vitro and cerebral ischemia in vivo. (2) Pro-oxidant insults cause persistent reductions in at least three protein phosphatases. (3) Persistent activation of these signaling kinases converts them into death-inducing kinases that contribute to oxidative damage, AD-like neuropathology and neuronal cell death. (4) Both feminizing and non-feminizing estrogens prevent the pro-oxidant induced persistent down regulation of protein phosphatases and the persistent activation of signaling kinases. Also, estrogens ameliorate neuronal death and AD neuropathology causes by persistent kinase activation. (5) Cerebral ischemia causes phosphatase decline, persistent kinase activation, progressive AD neuropathology, hippocampal damage and cognitive decline in young rats. (6) Persistent inhibition of protein phosphatases causes cognitive decline and tauopathy in young rats. Having demonstrated these normally functioning signaling pathways become, with persistent activation, death-inducing kinase pathways, we propose to determine the causative factors by (Aim 1) determining the mechanism by which chronic phosphatase inhibition causes cognitive and LTP decline and AD neuropathology; (Aim 2) determining the role of persistent kinase activation in AD neuropathology; (Aim 3) determining the role of induction of cyclin-dependent kinases in AD neuropathology; and determining the effects of E2 and non-feminizing estrogens on insult-induced AD-like neuropathology; (Aim 4) determining the mechanism by which estrogens ameliorate these changes; and ( Aim 5) determining the role of L-type Ca2+ channels in the estrogen up regulation of protein phosphatases. Collectively, these studies will determine the mechanism(s) by which oxidative events initiate and contribute to the progression of AD neuropathology and the extent to which estrogen can antagonize these effects of oxidative stress.

View original record on NIH RePORTER →