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).

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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).

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-MDCN-G (02))
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Petanceska, Suzana
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University of Kansas Lawrence
Schools of Pharmacy
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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
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