Mitochondrial and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD) affected brain1-7. Recent studies have highlighted the role of mitochondrial Abeta in AD pathogenesis. A progressively accumulates in mitochondria of AD brain and transgenic AD mice overexpressing Abeta. Notably, accumulation of mitochondrial Abeta precedes extracellular Abeta deposition in AD brain, which is consistent with the early onset of loss of synapses and synaptic and mitochondrial damage. Thus, accumulation of mitochondrial Abeta may be an initiating pathological event leading to mitochondrial and neuronal perturbation. Human PreP (hPreP) located in brain mitochondria, is a novel mitochondrial Abeta degrading enzyme. Our recent studies indicates that the proteolytic activity of hPreP was significantly reduced in Abeta-rich mitochondria from AD-affected brain and transgenic AD mice overexpressing APP/Abeta, suggesting that hPreP may potentially be of importance in preventing amyloid pathology of AD through its degradation and clearance of mitochondrial Abeta. However, the effects of PreP on amyloid pathology and mitochondrial and synaptic degeneration in Abeta milieu have not yet been disclosed. In our pilot studies, we observed the reduction of Abeta accumulation in mitochondria and cerebral cortex by increased PreP activity in Tg mAPP mice. We hypothesize that impaired function of PreP protease contributes to chronic mitochondrial Abeta accumulation relevant to developing amyloid pathology of AD, leading to mitochondrial and synaptic degeneration, thus, clearance of mitochondrial Abeta by PreP may be of importance in the pathology of AD. The goal of this proposal is to gain new insight into the role of PreP in AD pathogenesis, focusing on mitochondrial Abeta accumulation/clearance, amyloid pathology, synaptic mitochondrial properties, oxidative stress, synaptic function, utilizing a novel genetically manipulated transgenic mouse models and neuronal culture with altered PreP levels and proteolytic activity in Abeta-rich environment [(increased expression of neuronal PreP, inactive mutant PreP with catalytic base Glu(78) in the inverted zinc-binding motif replaced by Gln, lacking enzyme activity, and genetic deficiency of neuronal PreP in AD-type transgenic mice overexpressing Abeta). The outcomes of the project would also support that PreP might be a potential therapeutic agent for limiting mitochondrial and cerebral amyloid accumulation thereby halting AD progression.

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The aim of this project is to investigate an unexplored role of mitochondrial Abeta degrading enzyme (PreP) in mitochondrial amyloid pathology leading to synaptic mitochondrial and synaptic degeneration relevant to the pathogenesis of Alzheimer's disease. The outcomes of the proposed studies would also support that PreP might be a potential new therapeutic agent for eliminating and limiting mitochondrial and cerebral amyloid accumulation thereby halting progression of Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Petanceska, Suzana
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University of Kansas Lawrence
Schools of Pharmacy
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Criscuolo, Chiara; Fontebasso, Veronica; Middei, Silvia et al. (2017) Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model. Sci Rep 7:42370
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
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
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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
Huang, Shengbin; Wang, Yongfu; Gan, Xueqi et al. (2015) Drp1-mediated mitochondrial abnormalities link to synaptic injury in diabetes model. Diabetes 64:1728-42
Zhang, Zhihua; Wang, Yongfu; Yan, Shijun et al. (2015) NR2B-dependent cyclophilin D translocation suppresses the recovery of synaptic transmission after oxygen-glucose deprivation. Biochim Biophys Acta 1852:2225-2234
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

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