EFFECT OF A PPARγ SYNTHETIC AGONIST ASSOCIATED WITH RETINOIC ACID ON DAILY RHYTHMS OF RORα and REV-ERBβ IN AN EXPERIMENTAL MODEL OF ALZHEIMER DISEASE.

MAZZAFERRO P; GOLINI RS; CAMPOS LE; CASTRO A; ANZULOVICH AC; NAVIGATORE FONZO LS

San Luis

Congreso; XXXVII REUNION CIENTIFICA DE LA SOCIEDAD DE BIOLOGIA DE CUYO; 2019

Alzheimer's disease (AD) is the main cause of dementia in the aging population. It is characterized by a progressive cognitive declineand circadian rhythms alterations. At the molecular level, cellular oscillators consist of a network of interlocking transcriptionaltranslational feedback loops, a positive and a negative one. The positive loop is constituted by the heterodimer BMAL1: CLOCK andthe negative loop by phosphorylated PER-CRY complexes. RevErbα and RORα transcription factors, members of the retinoic acidrelated orphan receptor (ROR) family, complete the molecular clock machinery. Previously, we found that an i.c.v. injection ofAβ(1-42) modified the daily rhythms of RORα and REV-ERBβ expression in the rat hippocampus. Taking into account thoseobservations, the objective of this work was to investigate the effects of pioglitazone-retinoic acid (Pio-RA) on the rhythms of RORαand REV-ERBβ expression, as well as BMAL1 and Aβ protein levels, throughout a 24-h period, in the rat hippocampus. Fourmonth-old male Holtzman rats were divided into three groups defined as (1) control, (2) Aβ-injected, (3) Aβ-injected treated withPio-RA. Rats were maintained under 12 h-light:12 h-dark conditions and received water and food ad libitum. Tissues samples wereisolated every 6 h for a 24-h period. RORα and REV-ERBβ mRNA levels were determined by RT-PCR and Aβ and BMAL1 proteinlevels were analyzed by immunoblotting. We found that Pio-RA reestablished rhythmicity of those temporal patterns indicatingPPARγ-RXR heterodimer might be a transcription factor involved in circadian regulation and a potential target for the restoration oftemporal patterns of clock genes in AD.