Effects of Pioglitazone-Retinoic Acido n daily rhythms in an experimental model of Alzheimer disease

NAVIGATORE FONZO, LORENA; GARRAZA MARISA; RAGUSSA V; DELGADO S.M; ANZULOVICH, ANA CECILIA

Congreso; XXXII Reunión Anual de la Sociedad de Biologia de Cuyo,; 2014

Alzheimer?s disease (AD) is an age-related neurodegenerative disorder associated with impaired clearance of â-amyloid peptide (Aâ), a process normally facilitated by the apolipoprotein E (ApoE). ApoE expression is transcriptionally induced by the peroxisome proliferator?activated receptor gamma (PPARã) in coordination with retinoid X receptors (RXRs). On the other hand, besides the cognitive deficit, AD shows alteration in the circadian rhythms. Previously, we have demonstrated disruption of antioxidant enzymes circadian rhythms is associated with the increase of oxidative stress in vitamin A-deficient rats. Taking into account those observations, the objectives of this study were: first, to analyze the effect of an i.c.v. injection of Aâ(40-42) peptide on the 24h rhythms of Aâ and ApoE protein levels as well as on catalase (CAT) and glutathione peroxidase (GPx) activities in the rat hippocampus; second, to evaluate the effect of the PPARã agonist, pioglitazone, along to the RXR ligand, retinoic acid, on those temporal patterns. Four-month old males Holtzman rats were used in this study. Groups were defined as: 1) control 2) Aâ-injected 3) Aâ-injected treated with Pio-RA. Rats were maintained under 12h-Light:12h-Dark conditions. Aâ and ApoE proteins levels were analyzed by immunoblotting; CAT and GPx enzymatic activities were determined by kinetic assays; in hippocampus samples isolated every 6 h during a 24h period. We found that injection of Aâ(40-42) phase shifted Aâ, ApoE, CAT and GPx daily rhythms. Noteworthy, Pio-RA reestablished rhythmicity of those temporal patterns indicating PPARg-RXR heterodimer might be a transcription factor involved in circadian regulation and a potential target for restoration of circadian rhythmicity in neurodegenerative disorders.