Alzheimer's disease (AD) is one of the major health problems in the United States and as our population ages it will become more prominent unless measures to treat or prevent it are found. Understanding the pathogenesis of selective neuron degeneration in AD is the key to defining preventive or therapeutic measures. There is a rapidly increasing body of knowledge that indicates free radical-mediated oxidative damage is involved in the pathogenesis of AD. Our recent studies have demonstrated significant oxidative damage to brain lipids, proteins, DMA, and RNA in amnestic mild cognitive impairment, the earliest detectable phase of AD, indicating that oxidative damage is an early event in AD and not secondary to neurodegeneration. The major hypothesis of this proposal is that RNA oxidation in early AD is mediated in part by amyloid-beta peptide (AP) that promotes impairment of protein synthesis and neuron dysfunction.
In Specific Aims 1 and 2, we will quantify RNA oxidation and aldehydic modifications in neurons in the progression of AD from normal to MCI to late AD (LAD), and in the APP/PS1 knock-in transgenic mice over time using immunohistochemistry, confocal microscopy, and antibodies against 8-OHG, acrolein/guanine adducts, and MC-1. In the same brain regions of normal controls, disease controls (frontotemporal dementia), MCI and LAD, and brain specimens from APP/PS-1 mice, we will quantify RNA oxidation in purified pools of rRNA, tRNA, and mRNA by GC-MS-SIM and acrolein-modified guanine in these pools using LC-MS-MS.
In Specific Aim 3, we will determine the ability of toxic and non-toxic Ap from Core B to define RNA oxidation and acrolein/guanine adducts in cultured neurons and compare this with the RNA oxidation observed in vivo in Specific Aims 1 and 2.
In Specific Aim 4, we will determine if the individual mRNAs oxidized in response to Ap in vitro are also oxidized in the brains of control subjects and MCI, LAD, and frontotemporal dementia patients. We will then determine whether the predicted proteins encoded by the oxidized mRNAs exhibit decreased expression and function in the progression from normal to MCI to LAD.
Specific Aim 5 will define the ability of histone deacetylase inhibitors to ameliorate Ap-induced neurotoxicity in vitro and in the APP/PS1 transgenic mice. We have preliminary data in all specific aims indicating the feasibility of these studies. By conducting these studies in an unbiased manner and allowing the neurons and brain specimens to guide us, we will define how Ap promotes neuron dysfunction in AD. This study has the potential of identifying molecular targets for development of therapeutic agents aimed at reducing neuron injury and slowing the progression of or potentially preventing AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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University of Kentucky
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Ding, Qunxing; Zhu, Haiyan (2018) Upregulation of PSMB8 and cathepsins in the human brains of dementia with Lewy bodies. Neurosci Lett 678:131-137
Ellison, Elizabeth M; Abner, Erin L; Lovell, Mark A (2017) Multiregional analysis of global 5-methylcytosine and 5-hydroxymethylcytosine throughout the progression of Alzheimer's disease. J Neurochem 140:383-394
Hartz, Anika M S; Zhong, Yu; Wolf, Andrea et al. (2016) A?40 Reduces P-Glycoprotein at the Blood-Brain Barrier through the Ubiquitin-Proteasome Pathway. J Neurosci 36:1930-41
Butterfield, D Allan; Palmieri, Erika M; Castegna, Alessandra (2016) Clinical implications from proteomic studies in neurodegenerative diseases: lessons from mitochondrial proteins. Expert Rev Proteomics 13:259-74
Bradley-Whitman, Melissa A; Lovell, Mark A (2015) Biomarkers of lipid peroxidation in Alzheimer disease (AD): an update. Arch Toxicol 89:1035-44
Barone, Eugenio; Cenini, Giovanna; Di Domenico, Fabio et al. (2015) Basal brain oxidative and nitrative stress levels are finely regulated by the interplay between superoxide dismutase 2 and p53. J Neurosci Res 93:1728-39
Di Domenico, Fabio; Pupo, Gilda; Mancuso, Cesare et al. (2015) Bach1 overexpression in Down syndrome correlates with the alteration of the HO-1/BVR-a system: insights for transition to Alzheimer's disease. J Alzheimers Dis 44:1107-20
Chen, Chun-Hau; Li, Wenzong; Sultana, Rukhsana et al. (2015) Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease. Neurobiol Dis 76:13-23
Lovell, Mark A; Abner, Erin; Kryscio, Richard et al. (2015) Calcium Channel Blockers, Progression to Dementia, and Effects on Amyloid Beta Peptide Production. Oxid Med Cell Longev 2015:787805
Sethi, M; Joshi, S S; Webb, R L et al. (2015) Increased fragmentation of sleep-wake cycles in the 5XFAD mouse model of Alzheimer's disease. Neuroscience 290:80-9

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