EFFECTS OF PIOGLITAZONE-VALPROIC ACID ON DAILY RHYTHMS OF NEP EXPRESSION IN AN EXPERIMENTAL MODEL OF ALZHEIMER DISEASE

NAVIGATORE FONZO LS; CANGIANO B; CORTEZ M; GOLINI RS; ALBA R; ANZULOVICH AC

MODALIDAD VIRTUAL

Congreso; XXXIX REUNION CIENTIFICA DE LA SOCIEDAD DE BIOLOGIA DE CUYO; 2021

Alzheimer's disease (AD) is a primary cause of dementia in the elderly. AD late onset, which constitutes 90% of cases, couldbe mainly attributable to deficiencies in the clearance of the Aß peptide. Direct degradation of Aβ by endopeptidases hasemerged as one important pathway for clearance. Neprilysin (Nep) is one of the most important Abeta-degrading enzymes.Neurogranin (Rc3) and neuromodulin (Gap-43) play an important role in the learning and memory. Recently, PPAR-γagonists (Pioglitazone) have shown neuroprotective effects in neurodegenerative disorders. Numerous studies have shownthat the intraperitoneal administration of Valproic Acid (VA), an inhibitor of histone deacetylases, caused an increase in NEPactivity in different areas of the brain, including the hippocampus, in an experimental model of AD. AD patients also showalterations in their circadian rhythms. Taking into account these observations, the objective of this study was to evaluate theeffect of Pio/VA on the 24h rhythms of Aβ; Nep, Rc3 and Gap-43 expression in the hippocampus of Aβ-injected rats. Fourmonth-old males Holtzman rats were divided into three groups defined as: 1) control 2) Aβ-injected 3) Aβ-injected treatedwith Pio-VA. Rats were maintained under 12h-Light: 12h-Dark conditions. Tissues samples were isolated every 6 h duringa 24h period. Nep, Rc3 and Gap-43 mRNA levels were determined by RT-PCR. Aβ protein levels were analyzed byimmunoblotting. We found that the treatment of Pio-VA reestablished rhythmicity of those temporal patterns. These findingsmight constitute, at least in part, molecular and biochemical basis of restoration of circadian rhythmicity by the administrationof Pio-VA in neurodegenerative disorders.