There is increasing evidence that both mitochondrial dysfunction and oxidative damage contributes to Alzheimer's Disease (AD) pathogenesis. In our previous grant period, we found an increase in cytochrome oxidase mtDNA mutations in both aging and AD, and an increase in mtDNA mutations in the control region of mtDNA. There may be a direct interaction of amyloid-p peptide (A?) with Cu2+ to induce cytochrome oxidase dysfunction, and with the A? alcohol dehydrogenase within mitochondria to increase free radical generation. We propose to isolate mitochondria from both a double APR mutant and a triple transgenic mouse model of AD, to measure mitochondrial A? levels and to correlate levels with mitochondrial bioenergetics, free radical production, calcium uptake capacity and ability to activate the mitochondrial permeability transition. We will also determine APR cleavage and A? production in cultured neurons under conditions of increased or decreased mitochondrial dysfunction and oxidative stress. A partial deficiency of manganese superoxide dismutase (MnSOD), increases oxidative damage and exacerbates A? deposition in a transgenic mouse model of AD. We propose to cross a transgenic mouse model of AD with mice overexpressing MnSOD to determine whether this will ameliorate oxidative damage, A|3 deposition and spatial memory deficits. Lastly, we found that both coenzyme Q10 and genetic deficiency of NOS2 reduce A? deposition and improve survival of a transgenic mouse model of AD. We, therefore, propose to determine whether optimal administration of coenzyme Q10 and of a selective NOS 2 inhibitor can improve oxidative damage, A? deposition and spatial memory deficits in transgenic mouse models of AD. These studies will further define the role of mitochondrial dysfunction and oxidative damage in AD pathogenesis and have the potential of leading to important new therapies.
| Yao, Jiaqi; Ho, Daniel; Calingasan, Noel Y et al. (2012) Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J Exp Med 209:2501-13 |
| Elipenahli, Ceyhan; Stack, Cliona; Jainuddin, Shari et al. (2012) Behavioral improvement after chronic administration of coenzyme Q10 in P301S transgenic mice. J Alzheimers Dis 28:173-82 |
| Lin, Michael T; Cantuti-Castelvetri, Ippolita; Zheng, Kangni et al. (2012) Somatic mitochondrial DNA mutations in early Parkinson and incidental Lewy body disease. Ann Neurol 71:850-4 |
| Dumont, Magali; Kipiani, Khatuna; Yu, Fangmin et al. (2011) Coenzyme Q10 decreases amyloid pathology and improves behavior in a transgenic mouse model of Alzheimer's disease. J Alzheimers Dis 27:211-23 |
| Capetillo-Zarate, Estibaliz; Gracia, Luis; Yu, Fangmin et al. (2011) High-resolution 3D reconstruction reveals intra-synaptic amyloid fibrils. Am J Pathol 179:2551-8 |
| Tampellini, Davide; Rahman, Nawreen; Lin, Michael T et al. (2011) Impaired ?-amyloid secretion in Alzheimer's disease pathogenesis. J Neurosci 31:15384-90 |
| Dumont, Magali; Beal, M Flint (2011) Neuroprotective strategies involving ROS in Alzheimer disease. Free Radic Biol Med 51:1014-26 |
| Yao, Jiaqi; Hennessey, Tom; Flynt, Alex et al. (2010) MicroRNA-related cofilin abnormality in Alzheimer's disease. PLoS One 5:e15546 |
| Dumont, Magali; Wille, Elizabeth; Calingasan, Noel Y et al. (2010) N-iminoethyl-L-lysine improves memory and reduces amyloid pathology in a transgenic mouse model of amyloid deposition. Neurochem Int 56:345-51 |
| Tampellini, Davide; Capetillo-Zarate, Estibaliz; Dumont, Magali et al. (2010) Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer's disease transgenic mice. J Neurosci 30:14299-304 |
Showing the most recent 10 out of 23 publications
