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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG044793-01A1
Application #
8697949
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Petanceska, Suzana
Project Start
2014-08-15
Project End
2019-05-31
Budget Start
2014-08-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$380,000
Indirect Cost
$126,667
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
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
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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