EFFECTS OF PIOGLITAZONE-RETINOIC ACID ON DAILY RHYTHMS OF APO E IN AN EXPERIMENTAL MODEL OF ALZHEIMER DISEASE.

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

San Luis

Congreso; XXXVII REUNION CIENTIFICA DE LA SOCIEDAD DE BIOLOGIA DE CUYO; 2019

Alzheimer‟s disease (AD) late onset, which constitutes 90% of cases, could be mainly attributable to deficiencies in the clearance ofthe Aß. Apolipoprotein E (Apo E) is associated with age-related risk for Alzheimer‟s disease and plays a key role in facilitating theproteolytic clearance of Aβ from the brain. ApoE expression is transcriptionally induced by PPARγ in coordination with RXRs.Taking into account those observations, the objectives of this study were: first, to analyze the effect of an i.c.v. injection of Aβ(1-42)on the 24-h rhythms of Aβ, BMAL1, RORα, and ApoE protein levels in the rat prefrontal cortex (PC); second, to evaluate the effectof pioglitazone-retinoic acid (Pio-RA) on those temporal patterns. Four-month-old male Holtzman rats were divided into threegroups defined as: control, Aβ-injected (Aβ) and Aβ-injected treated with Pio-RA. Rats were maintained under 12 h-light:12 h-darkconditions before the sacrifice. Aβ, BMAL1, RORα, and ApoE proteins levels were analyzed by immunoblotting in PC samplesisolated every 6 h throughout a 24-h period. The regulatory region of Apo E was scanned for E-box, RORE, RXRE, and PPRE sites.We found that an i.c.v. injection of Aβ (1-42) modified the daily variation of ApoE, BMAL1, RORα, and Aβ protein in the ratprefrontal cortex. Also, we found E-box, RXRE, and PPRE sites on the regulatory region of the Apo E gene. The treatment of PioRA reestablished the rhythmicity of those temporal patterns. These findings might constitute, at least in part, the molecular basis ofthe restoration of daily rhythmicity of Apo E by the administration of Pio-AR in AD.