Abstract
Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of Aβ from the brain of transgenic mice model of Alzheimer’s disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPARγ co-activator 1α (PGC-1α), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPARγ agonist (ciglitazone) and a PPARα agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC-1α and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD.
Highlights
Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive memory loss and cognitive impairment [1,2]
These results suggest that CIG, through PPARc activation, is able to prevent the mitochondrial size reduction induced by oxidative stress, protecting neurons from H2O2induced mitochondrial altered fusion-fission process
Despite mitochondrial dysfunction has been recognized since long ago as a key event in Ab-induced neurotoxicity [12,18], only recently it has been established that mitochondrial dynamics plays a fundamental role in mediating mitochondrial dysfunction [19,33,34]
Summary
Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive memory loss and cognitive impairment [1,2]. No effective treatment is available to stop or reverses this devastating disease. Cramer et al [4] found that treatment with an old drug, bexarotene, reverses the cognitive deficit observed in a mice model of AD. Bexarotene, a retinoid related molecule, is an antineoplastic drug, approved by the FDA (U.S Food and Drug Administration) and the EMA (European Medicines Agency), for the treatment of some types of skin cancer [5,6]. Cramer et al [4] exploited the retinoid-based properties of bexarotene to activate the retinoid receptor (RXR) [5], inducing apolipoprotein E (ApoE), ABCA1 and ABCG1 expression, leading to enhanced Ab clearance from the brain. It is well recognized that ApoE4 is an increased-risk related ApoE isoform, and patients, who carries this variant, could not obtain any benefit, or worst, exhibits an even greater risk to develop AD or any other neuropathology [1,2,3]
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