Mitochondrial dysfunction and synaptic damage are early features of Alzheimer's disease (AD). Amyloid-? peptide (A?) has deleterious effects on mitochondrial and synaptic function and contributes to energy failure, respiratory chain impairment, increased production of reactive oxygen species (ROS), mitochondrial structure damage, and synaptic loss in AD. Mitochondrial membrane permeability transition pore (mPTP) is a key regulator for both necrotic and apoptotic cell death. Cyclophilin D (CypD), a peptidylprolyl isomerase F, resides in the mitochondria and plays a central role in opening the mitochondrial membrane permeability transition pore (mPTP) leading to cell death. We have demonstrated that CypD-mediated mPTP potentiates A?-induced mitochondrial malfunction and a decline in cognitive function in the AD mice. However, the mechanisms underlying CypD-mediated synaptic mitochondrial and cognitive abnormalities in an A? and oxidative stress milieu have not been fully elucidated. Based on our preliminary studies showing the involvement of CypD in A?-induced changes in mitochondrial distribution, function, synaptic loss, and PKA/CREB signal transduction pathway, we hypothesize that the CypD/A?-mediated mPTP interferes with synaptic mitochondrial trafficking, mitochondria dynamics and mitochondrial function, consequently, causing synaptic dysfunction and alternations in synaptic structure and transmission, which is likely to underlie impaired behavioral and electrophysiologic function. The goal of this proposal is to gain new insight into the role of CypD in A? -induced synaptic and neuronal stress, focusing on synaptic mitochondrial properties, oxidative stress, synapse and dendritic spine alternations, pre- and post-synaptic function, synaptic transmission, cAMP/PKA/CREB- associated signal transduction and neuronal function, utilizing a novel genetically manipulated transgenic mouse model and neuron culture (increased expression of neuronal CypD, and genetic deficiency of CypD in Tg mAPP mice).

Public Health Relevance

The goal of this proposal is to gain new insight into the role of CypD in A? -induced synaptic and neuronal stress, focusing on synaptic mitochondrial properties, oxidative stress, synapse and dendritic spine alternations, pre- and post-synaptic function, synaptic transmission, cAMP/PKA/CREB-associated signal transduction and neuronal function, utilizing a novel genetically manipulated transgenic mouse model and neuron culture (increased expression of neuronal CypD, and genetic deficiency of CypD in Tg mAPP mice).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37AG037319-03S2
Application #
8549346
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (02))
Program Officer
Snyder, Stephen D
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$5,000
Indirect Cost
$1,645
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Valasani, Koteswara Rao; Sun, Qinru; Fang, Du et al. (2016) Identification of a Small Molecule Cyclophilin D Inhibitor for Rescuing A?-Mediated Mitochondrial Dysfunction. ACS Med Chem Lett 7:294-9
Fang, Du; Yan, Shijun; Yu, Qing et al. (2016) Mfn2 is Required for Mitochondrial Development and Synapse Formation in Human Induced Pluripotent Stem Cells/hiPSC Derived Cortical Neurons. Sci Rep 6:31462
Fang, Du; Zhang, Zhihua; Li, Hang et al. (2016) Increased Electron Paramagnetic Resonance Signal Correlates with Mitochondrial Dysfunction and Oxidative Stress in an Alzheimer's disease Mouse Brain. J Alzheimers Dis 51:571-80
Fang, Du; Qing, Yu; Yan, Shijun et al. (2016) Development and Dynamic Regulation of Mitochondrial Network in Human Midbrain Dopaminergic Neurons Differentiated from iPSCs. Stem Cell Reports 7:678-692
Yan, Shijun; Du, Fang; Wu, Long et al. (2016) F1F0 ATP Synthase-Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline. Diabetes 65:3482-3494
Moskovitz, Jackob; Du, Fang; Bowman, Connor F et al. (2016) Methionine sulfoxide reductase A affects ?-amyloid solubility and mitochondrial function in a mouse model of Alzheimer's disease. Am J Physiol Endocrinol Metab 310:E388-93
Yu, Qing; Fang, Du; Swerdlow, Russell Howard et al. (2016) Antioxidants Rescue Mitochondrial Transport in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells. J Alzheimers Dis 54:679-90
Fang, Du; Wang, Yongfu; Zhang, Zhihua et al. (2015) Increased neuronal PreP activity reduces A? accumulation, attenuates neuroinflammation and improves mitochondrial and synaptic function in Alzheimer disease's mouse model. Hum Mol Genet 24:5198-210
Gan, Xueqi; Huang, Shengbin; Yu, Qing et al. (2015) Blockade of Drp1 rescues oxidative stress-induced osteoblast dysfunction. Biochem Biophys Res Commun 468:719-25
Carlson, Emily A; Marquez, Rebecca T; Du, Fang et al. (2015) Overexpression of 17?-hydroxysteroid dehydrogenase type 10 increases pheochromocytoma cell growth and resistance to cell death. BMC Cancer 15:166

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