EFFECTS OF PIOGLITAZONE-RETINOIC ACID ON THE 24H RHYTHMS OF COGNITION-RELATED FACTORS IN AN EXPERIMENTAL MODEL OF ALZHEIMER DISEASE

CORIA LUCERO, C; LEDEZMA, C; CASTRO A; LEPORATTI, J; ANZULOVICH AC; DELGADO SM; NAVIGATORE FONZO LS

MODALIDAD VIRTUAL

Congreso; IV REUNIÓN CONJUNTA DE LAS SOCIEDADES DE BIOLOGIA DE ARGENTINA; 2020

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function and also disruption of circadianrhythms. Synthetic PPARγ agonists such as pioglitazone have been shown to improve cognitive performance in patients with AD. Previous studiesindicate that retinoic acid rescues memory deficits in an Alzheimer's disease model. Previously, we found that an intracerebroventricular injection ofAβ(1-42) modified the daily rhythms of cognition related factors in the rat temporal cortex (TC). We also found E-box sites on regulatory region ofBdnf and TrkB genes. Taking into account those observations, the objectives of this study were: first, to investigate the effects of pioglitazoneretinoic acid (Pio-RA) on the daily rhythms of Bdnf and Trkβ expression, as well as on the 24-h rhythms of clock protein levels; second, to evaluatethe effect of Pio-RA on cognitive performance. Four-month-old male Holtzman rats were divided into three groups defined as: (1) control, (2) Aβinjected, (3) Aβ-injected treated with Pio-RA. Rats were maintained under 12 h light:12 h dark conditions and received water and food ad libitum.Bdnf and Trkβ mRNA levels were determined by RT-PCR and clock protein levels were analyzed by immunoblotting in TC samples isolated every 6h throughout a 24-h period. Regulatory regions of Bdnf and TrkB were scanned for RXRE and PPRE sites. The cognitive function was evaluated byBarnes test. We found that the day-night oscillation of factors related to cognition was maintained in the Aβ-injected animals treated with Pio-RAand that the treatment increased the levels of Bdnf and its receptor mRNA levels. Such an increase could be fundamental for synaptic plasticity. Wealso observed that treatment of Pio-RA reestablished the daily rhythms of the clock’s protein and improved cognitive disorders. These findingssuggest that the administration of Pio-RA would be a novel therapeutic strategy for Alzheimer's disease.