CONSEQUENCES OF PIOGLITAZONE-RETINOIC ACID ADMINISTRATION ON DAILY RHYTHMS OF TNFα, IN AN EXPERIMENTAL MODEL OF ALZHEIMER’S DISEASE

LEDEZMA, C; CORIA LUCERO, C; DELGADO SM; ANZULOVICH AC; NAVIGATORE FONZO LS

MODALIDAD VIRTUAL

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

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder. The neuronal dysfunction and cell death mechanisms that are commonlyfound in this disease are due to the production of high levels of cytokines, TNFα among them, the formation of amyloid plaques and the alteration ofthe circadian rhythms. Due to the etiology of AD, multi-target therapies could be more effective. Both PPARγ agonist and retinoids are goodcandidates for this approach, since they regulate a large number of keys genes and proteins in various pathways, including neurotransmission, Aβ,inflammation, neurogenesis and circadian synchronization, among others. Previously, we found that an intracerebroventricular injection of Aβ (1-42)modified the daily rhythms of TNFα and clock proteins in the rat prefrontal cortex. Taking into account those observations, the objective of this studywas, to evaluate the effect of the PPARγ agonist, pioglitazone, along to the RXR ligand, retinoic acid, on the 24-h rhythms of Aβ, ApoE, and clockprotein. Four-month-old males Holtzman rats were used in this study. Groups were defined as: (1) control, (2) Aβ-injected, (3) Aβ-injected treatedwith Pioglitazone-Retinoic Acid (Pio-RA). Rats were maintained under 12 h light:12 h dark conditions with food ad libitum. Aβ, ApoE, BMAL1,and RORα proteins levels were analyzed by immunoblotting in prefrontal cortex samples isolated every 6 h during a 24-h period. We found that thetreatment of Pio-RA reestablished rhythmicity of clock and TNFα proteins and decreased Aβ levels in the rat prefrontal cortex. These findings couldindicate that PPARg-RXR heterodimer might be a potential target for restoration of circadian rhythmicity in neurodegenerative disorders.