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 #
3R37AG037319-05S1
Application #
8890943
Study Section
Special Emphasis Panel (ZRG1-MDCN-G (02))
Program Officer
Petanceska, Suzana
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2014-08-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$5,000
Indirect Cost
$1,598
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Yan, Shi Fang; Akhter, Firoz; Sosunov, Alexander A et al. (2018) Identification and Characterization of Amyloid-? Accumulation in Synaptic Mitochondria. Methods Mol Biol 1779:415-433
Fang, Fang; Yu, Qing; Arancio, Ottavio et al. (2018) RAGE mediates A? accumulation in a mouse model of Alzheimer's disease via modulation of ?- and ?-secretase activity. Hum Mol Genet 27:1002-1014
Kalani, Komal; Yan, Shi Fang; Yan, Shirley ShiDu (2018) Mitochondrial permeability transition pore: a potential drug target for neurodegeneration. Drug Discov Today 23:1983-1989
Du, Fang; Yu, Qing; Chen, Allen et al. (2018) Astrocytes Attenuate Mitochondrial Dysfunctions in Human Dopaminergic Neurons Derived from iPSC. Stem Cell Reports 10:366-374
Akhter, F; Chen, D; Yan, S F et al. (2017) Mitochondrial Perturbation in Alzheimer's Disease and Diabetes. Prog Mol Biol Transl Sci 146:341-361
Yu, Qing; Du, Fang; Douglas, Justin T et al. (2017) Mitochondrial Dysfunction Triggers Synaptic Deficits via Activation of p38 MAP Kinase Signaling in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells. J Alzheimers Dis 59:223-239
Du, Fang; Yu, Qing; Yan, Shijun et al. (2017) PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease. Brain 140:3233-3251
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
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; 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

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