EFFECT OF A PPARγ SYNTHETIC AGONIST ASSOCIATED WITH VALPROIC ACID ON THE 24-HOUR RHYTHMS OF INSULIN-DEGRADING-ENZYME IN AN EXPERIMENTAL MODEL OF ALZHEIMER'S DISEASE

SÁNCHEZ MELISA; CANGIANO BELEN; CORTEZ MAYRA; GOLINI REBECA; ALBA R; GARRAZA MARISA; ANZULOVICH, AC; NAVIGATORE FONZO LORENA

Mendoza

Congreso; XL REUNION CIENTIFICA ANUAL DE LA SOCIEDAD DE BIOLOGIA DE CUYO; 2022

SOCIEDAD DE BIOLOGIA DE CUYO

Alzheimer’s disease (AD) is the most common form of age-related neurodegenerative disorder. Numerous studies has shown that an imbalance between the production and clearance of amyloid-β (Aβ) peptides in the brain results in accumulation of Aβ. It is known that insulin-degrading-enzyme (IDE) plays a crucial role in the clearance of Alzheimer´s amyloid-β (Aβ). Numerous studies have shown that Pioglitazone (Pio), PPAR-γ agonists, possess antioxidant properties and improve cognitive deficits in AD. Valproic acid (VPA), a multifunctional drug plays important roles in promoting the release of neurotrophic factor and improve memory déficits. In addition,evidences show that the molecular clock function depends on the cellular redox state. Previously, we found that the treatment of Pio-VPAreestablished rhythmicity of oxidative stress parameters in the hippocampus. Taking into account these observations, the objective of this study was to evaluate the effect of Pio/VPA on the 24h rhythms of Aβ; IDE, BDNF and its receptor in the hippocampus of Aβ-injected rats. Four-month-old male Holtzman rats were divided into three groups defined as:1)control 2)Aβ-injected 3)Aβ-injected treated with Pio-VPA. Rats were maintained under 12h-light:12h-dark conditions and received water and food ad libitum. Hippocampus samples were isolated every 6 h during a 24h period. Transcript levels of insulin-degrading-enzyme and cognition-related factors were determined by RT-PCRand Aβ protein by immunoblotting. We found that injection of Aβ(1-42) phase shifted Aβ, IDE and BDNF/TrkB rhythms. Noteworthy, Pio-VPA reestablished rhythmicity of those temporal patterns. Thus, combination therapy with pioglitazone and valproic acid ameliorates pathologic changes observed in an experimental model of AD and might represent a potential treatment approach for AD.