Proteasome impairment, mitochondria dysfunction, and TAU pathology in Alzheimer disease
Item
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Title
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Proteasome impairment, mitochondria dysfunction, and TAU pathology in Alzheimer disease
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Identifier
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d_2009_2013:173729e4f275:11497
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identifier
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11971
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Creator
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Huang, Qian,
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Contributor
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Maria E. Figueiredo-Pereira
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Date
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2012
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biochemistry | Neurosciences
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Abstract
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There are no current treatments that are neuroprotective in the sense that they slow or prevent further neurodegeneration in AD. To provide new insights for the development of novel and more effective therapeutic strategies that prevent/stop neurodegeneration in AD, the MAJOR AIMS of these studies were: (1) Investigate underlying mechanisms that link mitochondrial dysfunction to impairment of the ubiquitin/proteasome pathway. (2) Evaluate the protective effect of elevating cAMP against an endogenous product of inflammation, i.e. prostaglandin J2 that affects the ubiquitin/proteasome pathway.;In our studies we used rat E18 cerebral cortical neuronal cultures to investigate the pathogenesis of Alzheimer's disease (AD).;For the FIRST AIM, we mimicked mitochondrial dysfunction by treating neurons with the following mitochondrial toxins: (1) oligomycin which inhibits ATP synthase, (2) rotenone which inhibits mitochondrial complex I, and (3) antimycin which inhibits mitochondrial complex III.;Overall, these data support the notion that upon mitochondrial dysfunction, neurons initiate a series of mechanisms that converge to optimize unregulated and energy-independent turnover of randomly unfolded oxidized proteins by 20S proteasomes. This adaptive response to energy deficiency may be suitable for short-term periods. However, if maintained chronically it may lead to neurodegeneration, as regulated protein degradation by the ubiquitin/proteasome pathway is essential for neuronal survival.;For the SECOND AIM, we treated rat E18 cerebral cortical neurons with prostaglandin J2 (PGJ2), an endogenous product of inflammation that affects mitochondrial function, and inhibits the 26S proteasome by causing its disassembly. We compared the effects of PGJ2 with those of the specific and irreversible proteasome inhibitor epoxomicin. We show that treatment with both drugs induces caspase-activation, TAU cleavage at Asp421 (DeltaTAU), TAU and Ub-protein aggregation, and neuronal death. Truncation of TAU at Asp421 (DeltaTAU) by caspases is an early event in AD tangle pathology. In addition, DeltaTAU is detected in neurofibrillary tangles (NFTs) indicating that the apoptotic cascade is involved in NFT formation.;To prevent these deleterious events associated with proteasome inhibition, we tested two drugs that elevate intracellular cAMP: dibutyryl-cAMP (db-cAMP) and the lipophilic peptide PACAP27 that increases intracellular cAMP levels by binding to its seven transmembrane G-coupled receptor PAC1R. Previous studies from our lab showed that a single dose of db-cAMP or PACAP27, blocked caspase-activation and DeltaTAU upon short-term (up to 8h) treatment with PGJ2. One single dose of these cAMP-elevating drugs however, failed to protect against longer (24h) treatments with PGJ2. In our current studies, we decided to increase the number of drug treatments to improve protection. We established that three doses of either db-cAMP or PACAP27 successfully diminished caspase-activation, DeltaTAU and loss of cell viability promoted by long-term (24h) incubations, as long as these changes were mild. Based on these studies, we propose that targeting cAMP/PKA to boost proteasome activity in a sustainable manner, could offer an effective approach to avoid early accumulation of ubiquitinated proteins and later caspase-activation and TAU cleavage, possibly preventing/delaying neurodegeneration in AD. (Abstract shortened by UMI.).
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
