Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Amyloid-? peptide (A?) has deleterious effects on mitochondrial function and contributes to respiratory chain impairment, energy failure, generation of reactive oxygen species (ROS), and neuronal apoptosis in AD. Recent studies have highlighted the pivotal role of mitochondrial A? in Alzheimer's disease pathogenesis. Cyclophilin D (CypD), a peptidylprolyl isomerase F, resides in the mitochondrial matrix and associates with the inner mitochondrial membrane during the mitochondrial membrane permeability transition (mPT). CypD plays a central role in opening the mitochondrial membrane permeability transition pore (mPTP) leading to cell death. The level of CypD was significantly elevated in neurons in AD-affected regions. We have demonstrated the presence of CypD-A? complex in the cortical mitochondria of AD brain and Tg mAPP mice, and the binding of recombinant CypD protein to A? with surface plasmon resonance (SPR). CypD deficiency (lacking A? binding partner) protected against A? -mediated mitochondrial and synaptic dysfunction. Further, our pilot studies showed that increased expression of CypD (enhancing CypD- A? interaction) exacerbated mitochondrial and neuronal perturbation as well as early onset of deficits in spatial learning/memory. These studies lead us to hypothesize that CypD is a critical mitochondrial target potentiating A?-mediated mitochondrial and neuronal dysfunction. Blockade of the CypD-A? interaction will attenuate A?-induced mitochondrial and neuronal perturbation. The goal of this project is to elucidate the basis of CypD-A? interaction using crystal (Aim 1) and NMR (Aim 2) structural analyses, and to analyze critical aspects of the intracellular pathway through which engagement of CypD with A? induces mitochondrial and neuronal dysfunction (Aim 3). The proposed research is highly significant and innovative on three points. First, the expected outcomes will reveal the structural details of CypD with A? at atomic resolution, which has never been reported. Second, the consequence of CypD-A? interaction in A?-mediated mitochondrial and neuronal dysfunction will be elucidated based on structural and functional analysis. Third, the results of this proposal will have a profound impact on the AD field by establishing a new target for preventive and therapeutic intervention.

Public Health Relevance

The goal of this project is to elucidate the basis of CypD-A? interaction using crystal and NMR structural analyses, and to analyze critical aspects of the mitochondrial pathway through which engagement of CypD with A? induces mitochondrial and neuronal damages. The results of this proposal will have a profound impact on the AD field by establishing a new target for preventive and therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095355-05
Application #
8544480
Study Section
Special Emphasis Panel (ZRG1-MDCN-B (02))
Program Officer
Wehrle, Janna P
Project Start
2010-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$363,377
Indirect Cost
$79,214
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Vangavaragu, Jhansi Rani; Valasani, Koteswara Rao; Gan, Xueqi et al. (2014) Identification of human presequence protease (hPreP) agonists for the treatment of Alzheimer's disease. Eur J Med Chem 76:506-16
Du, Heng; Guo, Lan; Wu, Xiaoping et al. (2014) Cyclophilin D deficiency rescues A*-impaired PKA/CREB signaling and alleviates synaptic degeneration. Biochim Biophys Acta 1842:2517-27
Gan, Xueqi; Huang, Shengbin; Wu, Long et al. (2014) Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cell. Biochim Biophys Acta 1842:220-31
Valasani, Koteswara Rao; Vangavaragu, Jhansi Rani; Day, Victor W et al. (2014) Structure based design, synthesis, pharmacophore modeling, virtual screening, and molecular docking studies for identification of novel cyclophilin D inhibitors. J Chem Inf Model 54:902-12
Valasani, Koteswara Rao; Carlson, Emily A; Battaile, Kevin P et al. (2014) High-resolution crystal structures of two crystal forms of human cyclophilin D in complex with PEG 400 molecules. Acta Crystallogr F Struct Biol Commun 70:717-22
Valasani, Koteswara Rao; Chaney, Michael O; Day, Victor W et al. (2013) Acetylcholinesterase inhibitors: structure based design, synthesis, pharmacophore modeling, and virtual screening. J Chem Inf Model 53:2033-46
Valasani, Koteswara R; Hu, Gang; Chaney, Michael O et al. (2013) Structure-based design and synthesis of benzothiazole phosphonate analogues with inhibitors of human ABAD-Aýý for treatment of Alzheimer's disease. Chem Biol Drug Des 81:238-49