Mitochondrial and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD) affected brain. The underlying mechanisms and strategies to repair it remain unclear. Recent studies have highlighted the role of mitochondrial A and early synaptic mitochondrial defects in AD pathogenesis. The early synaptic mitochondrial damage suggests that AD neurons may have already suffered harm for years, which may help explain the limitations to current amyloid hypothesis. Thus, strategies that suppress/attenuate AD- and A-induced mitochondrial toxicity in addition to A levels in the brain and improve cognitive function are critical for preventing and/or halting AD at a very early stage by improving mitochondrial function. Cyclophiiin D (CypD) plays a central role in opening the mitochondrial membrane permeability transition pore (mPTP) leading to cell death. CypD- mediated mPTP potentiates A- and oxidative stress-induced mitochondrial, synaptic, and cognitive dysfunction in the AD mouse model. Abrogation of CypD results in persistent life-long protection against A toxicity in an AD mouse model, suggesting that CypD is a potential target of the drug development for AD therapy. However, a direct link of CypD to AD-derived mitochondrial defects remains elusive. It is unclear whether CypD-potentiated mPTP and signal transduction contribute to AD-related mitochondrial defects including alterations in mitochondrial morphology, dynamics, and function, how CypD regulates mitochondrial dynamics, and whether blocking CypD rescues AD mitochondrial injury. To explore the mechanism associated with AD-specific mitochondrial defects, we have recently generated transmitochondrial cytoplasmic hybrid (cybrid) neuronal cell lines with incorporated platelet mitochondria from MCI, AD, and cognitively normal aged-matched subjects into mitochondrial DNA {mtDNA)-depleted neuronal cells. These human AD cybrid neuronal lines recapitulate mitochondrial structural and functional changes observed in AD. We found increased expression of CypD in MCI and AD cybrid cells. Importantly, blockade of CypD expression or inhibiting CypD activity restored mitochondrial morphology, dynamics (fusion/fission balance) and function in AD cybrid cells. We hypothesize that CypD-mediated mPTP alters mitochondrial distribution/morphology and function, balance of mitochondrial dynamics, which is likely to underlie AD-related mitochondrial and synaptic defects. Blockade of CypD will have a protective effect on mitochondrial and synaptic injury. The overall goal of this project is to gain new insight into the role of CypD in AD specific mitochondrial defects and to explore/validate a new class of small molecule CypD inhibitor for rescuing mitochondrial and cognitive dysfunction. The outcomes of this project will have a significantly high impact on the AD research field by identifying new targets for preventive and therapeutic intervention.

Public Health Relevance

The overall goal of this project is to gain new insight into the role of CypD in AD specific mitochondrial defects and to explore/validate a new class of small molecule CypD inhibitor for rescuing mitochondrial and cognitive dysfunction. We will utilizing novel transmitochondrial MCI and AD cybrid neuronal cell lines, novel CypD transgenic mice, and the disease phenotypes of AD mouse model producing A in neurons to,evaluate the biological activity of small molecule CypD inhibitor.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG037319-08
Application #
9292211
Study Section
Special Emphasis Panel (NSS)
Program Officer
Opanashuk, Lisa A
Project Start
2010-07-01
Project End
2020-05-31
Budget Start
2017-07-01
Budget End
2018-05-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Type
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
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
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
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

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