Validating Lxrs/ABCA1/ApoE AXIS Intervention As a Potential Therapeutic Taget to Prevent Amyloid Beta Clearance Imbalance.

M EUGENIA NAVAS GUIMARAES; M. BEATRIZ BISTUÉ MILLÓN, ; MARTIN A BRUNO

Chicago

Conferencia; AAIC; 2018

Alzheimer Association USA

Background: The progressive accumulation of amyloid beta (Aβ) in specific areas of the brain of patient with sporadic Alzheimer?s diseases (AD) starts as a result of an imbalance between the Aβ production and degradation, initiating a failure in Aβ drainage and consequently its deposition. The most relevant described process regarding Aβ clearance from the brain is through ApoE, which may modulate Aβ removal from the brain to the systemic circulation by transport across the blood-brain barrier (BBB). The interaction between ApoE and Aβ is conditioned by the correct lipidation of ApoE, which is induced by ABCA1. Both are modulated by cerebral expression of liver X receptors (LXRs). The present study is aimed to validate the LXRs/ABCA1/ApoE axis intervention as potential therapeutic target in AD. Methods: A novel LXRs agonist called DMHCA is being tested, described previously to display undetectable undesired side effects but not/reduced BBB penetration. DMHCA was encapsulated in a PEGylated dendrimer and used as nanocarrier. Primary cell culture from rat cerebral cortex was used to analyze cellular uptake and specific effect of the DMHCA-loaded nanocarrier. Co-localization images were obtained at confocal microscopy, whereas biotin was incorporated to the nanocarrier. To assess the biological effects on specific targets, ABCA1 and ApoE were measured by western blot after 2 and 24hs of treatment post DMHCA-loaded dendrimer. Results: Based on confocal and biochemical studies, we observed that the Biotin-PEG[G1]-DMHCA nanocarrier effectively penetrate neuronal and glial cells. Furthermore, PEG[G1]-DMHCA upregulate LXR´s target proteins, that are crucial for Aβ clearance process. Conclusion: Age-related impairment of Aβ homeostatic mechanisms has been postulated to be a critical determinant of disease risk. Aβ peptides are normally generated at high levels in the brain and are cleared at an equivalent rate in both humans and rodents. Thus, even modest reductions in clearance of soluble Aβ could result in elevated levels of Aβ peptides and ultimately their progressive and chronic deposition within the brain. Our in vitro studies positively validate the LXRs/ABCA1/ApoE axis as potential target to prevent in vivo Aβ accumulation. DMHCA-loaded dendrimer intranasal administration, mouse brain distribution and specific in vivo brain effects are under investigation.