Effect of a PPAR-γ synthetic agonist associated with retinoic acid on daily rhythms of RORα and REV-erbß in an experimental model of Alzheimer disease

MAZAFERRO P; GOLINI R; CAMPOS LE; CASTRO A; ANZULOVICH AC; NAVIGATORE FONZO L

San Luis capital

Congreso; XXXVII Reunión Científica Annual de la Sociedad de Biología de Cuyo (SBC); 2019

Sociedad de Biología de Cuyo

Alzheimer's disease (AD) is the main cause of dementia in the aging population. It is characterized by a progressive cognitive decline and circadian rhythms alterations. At the molecular level, cellular oscillators consist of a network of interlocking transcriptionaltranslational feedback loops,a positive and anegative one. The positive loop is constituted by the heterodimer BMAL1: CLOCKand the negative loop by phosphorylated PER-CRY complexes. RevErbα and RORα transcription factors, members of the retinoic acid related orphan receptor (ROR) family, complete the molecular clock machinery. Previously, we found thatan i.c.v. injection of Aβ(142) modified the daily rhythms of RORα and REV-ERBβexpression in the rat hippocampus. Taking into account those observations, the objective of this work was to investigate the effects of pioglitazone-retinoic acid (Pio-RA) on the rhythms of RORα and REVERBβ expression, as wellas BMAL1 and Aβ protein levels, throughout a 24 h period, in the rat hippocampus. Four-month-old male Holtzman rats were divided into three groups defined as:1)control 2)Aβ-injected 3)Aβ-injected treated with Pio-RA. Rats weremaintained under12h-light:12h-dark conditions and received water and food ad libitum. Tissues samples were isolated every 6 h during a 24h period. RORα and REV-ERBβ mRNA levels were determined by RT-PCR and Aβ and BMAL1 protein levels were analyzed by immunoblotting. We found that Pio-RA reestablished rhythmicity of those temporal patterns indicating PPARγ-RXR heterodimer might be a transcription factor involved in circadian regulation and a potential target for restoration of temporal patterns of clock genes in AD.