Oxidative damage is a key feature in the brain of Alzheimer's disease (AD) patients. In one well- studied mouse model of AD, Tg2576 mice that overexpress a double mutant form of amyloid precursor protein (APP), amyloid plaque deposition was shown to be associated with oxidative damage. In addition, these AD model mice exhibited diminished axon transport in vivo, as measured by manganese enhanced magnetic resonance imaging, long-term potentiation (LTP), and impaired hippocampus-dependent memory. We recently have found that scavenging mitochondrial superoxide by overexpression of mitochondrial superoxide dismutase (SOD-2) can prevent the aforementioned abnormalities. Although these are extremely exciting findings, it is not clear how preventing oxidative stress originating from mitochondria can reverse nearly all of the cellular and behavioral phenotypes in the Tg2576 mice. One possibility is that overexpression of SOD-2 prevents increased phosphorylation of the translation initiation factor eIF2?. Phosphorylation of eIF2? results in an inhibition of general protein synthesis, and it was shown recently that eIF2? phosphorylation is elevated in the hippocampus of Tg2576 mice. Importantly, it also was shown that the increased eIF2? phosphorylation exhibited by the Tg2576 mice could be prevented by the anti-oxidant vitamin E. Therefore, we examined the levels of eIF2? phosphorylation in Tg2576 mice that were crossed with the transgenic mice that overexpress SOD-2. Our preliminary data indicate that overexpression of SOD-2 prevents the increased eIF2? phosphorylation in the brains of Tg2576 mice. These exciting preliminary findings have prompted us to hypothesize that preventing increased eIF2? phosphorylation will prevent A?-induced blockade of LTP in vitro and reverse the aforementioned impairments in LTP and hippocampus-dependent memory displayed by the Tg2576 mice in vivo. To test this hypothesis, we will 1) determine whether A?-induced blockade of LTP requires reactive oxygen species (ROS) produced via mitochondria and/or NADPH oxidase, 2) determine whether A? induces ROS-dependent increases in eIF2? phosphorylation via mitochondria and/or NADPH oxidase, 3) determine whether A?-induced blockade of LTP requires eIF2? phosphorylation via PERK, and 4) determine whether genetic reduction of eIF2? phosphorylation prevents impairments in hippocampal LTP and memory displayed by Tg2576 mice. The results of these experiments should provide crucial information concerning whether PERK- eIF2? signaling is a target of oxidative stress in AD. Such information should be useful in developing pharmacological and therapeutic strategies for treatment of not only AD, but also other neurodegenerative diseases that involve oxidative stress and alterations in protein synthesis.

Public Health Relevance

The overall goal of the proposed work in this application is to determine the source and mechanisms responsible for oxidative stress-induced impairments in synaptic plasticity and memory in models of Alzheimer's disease, the most common form of dementia in older individuals. It is estimated that 5.2 million people in the United States are living with Alzheimer's disease and 10 million baby boomers will develop the disease in their lifetime. Current costs of Alzheimer's are estimated to be $148 billion per year. We have proposed experiments to determine specific targets of oxidative stress that impact protein synthesis, and will use pharmacological and genetic approaches to reverse A?-induced impairments in synaptic plasticity in vitro and synaptic plasticity and memory impairments in vivo in mice that model Alzheimer's disease. These studies have the potential to identify several new therapeutic targets for the treatment of Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034007-19
Application #
8089508
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (03))
Program Officer
Talley, Edmund M
Project Start
1995-05-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
19
Fiscal Year
2011
Total Cost
$324,188
Indirect Cost
Name
New York University
Department
Neurology
Type
Schools of Arts and Sciences
DUNS #
041968306
City
New York
State
NY
Country
United States
Zip Code
10012
Huynh, T N; Santini, E; Mojica, E et al. (2018) Activation of a novel p70 S6 kinase 1-dependent intracellular cascade in the basolateral nucleus of the amygdala is required for the acquisition of extinction memory. Mol Psychiatry 23:1394-1401
Santini, Emanuela; Huynh, Thu N; Longo, Francesco et al. (2017) Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice. Sci Signal 10:
Ostroff, Linnaea E; Botsford, Benjamin; Gindina, Sofya et al. (2017) Accumulation of Polyribosomes in Dendritic Spine Heads, But Not Bases and Necks, during Memory Consolidation Depends on Cap-Dependent Translation Initiation. J Neurosci 37:1862-1872
Bowling, Heather; Bhattacharya, Aditi; Klann, Eric et al. (2016) Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology. Neural Regen Res 11:363-7
Yang, Wenzhong; Zhou, Xueyan; Zimmermann, Helena R et al. (2016) Repression of the eIF2? kinase PERK alleviates mGluR-LTD impairments in a mouse model of Alzheimer's disease. Neurobiol Aging 41:19-24
Bhattacharya, Aditi; Mamcarz, Maggie; Mullins, Caitlin et al. (2016) Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice. Neuropsychopharmacology 41:1991-2000
Bowling, Heather; Bhattacharya, Aditi; Zhang, Guoan et al. (2016) BONLAC: A combinatorial proteomic technique to measure stimulus-induced translational profiles in brain slices. Neuropharmacology 100:76-89
Sethna, Ferzin; Zhang, Ming; Kaphzan, Hanoch et al. (2016) Calmodulin activity regulates group I metabotropic glutamate receptor-mediated signal transduction and synaptic depression. J Neurosci Res 94:401-8
Huynh, Thu N; Shah, Manan; Koo, So Yeon et al. (2015) eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors. Neurobiol Dis 83:67-74
Gross, Christina; Chang, Chia-Wei; Kelly, Seth M et al. (2015) Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep 11:727-36

Showing the most recent 10 out of 52 publications