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 S; NAVIGATORE FONZO L

San Luis capital

Congreso; XXXVII Reunión Científica Annual de la Sociedad de Biología de Cuyo (SBC); 2019

Sociedad de Biología de Cuyo

Alzheimer disease (AD) late onset, which constitutes 90% of cases, could be mainly attributable to deficiencies in the clearance of the Aß. Apolipoprotein E (Apo E) is associated with age-related risk for Alzheimer?s disease and plays a key role in facilitating the proteolytic 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 24h rhythms of Aβ, BMAL1, RORα and ApoE protein levels in the rat prefrontal cortex (PC); second, to evaluate the effect of pioglitazone-retinoic acid (Pio-RA) on those temporal patterns. Four-month-old male Holtzman rats were divided into three groups defined as: control, Aβ-injected (Aβ) and Aβ-injected treated with Pio-RA. Rats were maintained under 12h-light:12h-dark conditions before the sacrifice. Aβ, BMAL1, RORα and ApoE proteins levels were analyzed by immunoblotting in PC samples isolated every 6 h throughout a 24h period. 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 rat prefrontal cortex. Also we found E-box, RXRE, and PPRE sites on regulatory region of Apo E gen. The treatment of Pio-RA reestablished rhythmicity of those temporal patterns. These findings might constitute, at least in part, molecular basis of restoration of daily rhythmicity of Apo E by the administration of Pio-AR in AD.