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Liver X Receptor Activation with an Intranasal Polymer Therapeutic Prevents Cognitive Decline without Altering Lipid Levels
- Source :
- ACS Nano, Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela, instname, CONICET Digital (CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, instacron:CONICET
- Publication Year :
- 2021
-
Abstract
- The progressive accumulation of amyloid-beta (Aβ) in specific areas of the brain is a common prelude to late-onset of Alzheimer's disease (AD). Although activation of liver X receptors (LXR) with agonists decreases Aβ levels and ameliorates contextual memory deficit, concomitant hypercholesterolemia/hypertriglyceridemia limits their clinical application. DMHCA (N,N-dimethyl-3β-hydroxycholenamide) is an LXR partial agonist that, despite inducing the expression of apolipoprotein E (main responsible of Aβ drainage from the brain) without increasing cholesterol/triglyceride levels, shows nil activity in vivo because of a low solubility and inability to cross the blood brain barrier. Herein, we describe a polymer therapeutic for the delivery of DMHCA. The covalent incorporation of DMHCA into a PEG-dendritic scaffold via carboxylate esters produces an amphiphilic copolymer that efficiently self-assembles into nanometric micelles that exert a biological effect in primary cultures of the central nervous system (CNS) and experimental animals using the intranasal route. After CNS biodistribution and effective doses of DMHCA micelles were determined in nontransgenic mice, a transgenic AD-like mouse model of cerebral amyloidosis was treated with the micelles for 21 days. The benefits of the treatment included prevention of memory deterioration and a significant reduction of hippocampal Aβ oligomers without affecting plasma lipid levels. These results represent a proof of principle for further clinical developments of DMHCA delivery systems. Fil: Navas Guimaraes, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; Argentina Fil: Lopez Blanco, Roi. Universidad de Santiago de Compostela; España Fil: Correa, Juan. Universidad de Santiago de Compostela; España Fil: Fernandez Villamarin, Marcos. Universidad de Santiago de Compostela; España Fil: Bistue Millon, Maria Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; Argentina Fil: Martino Adami, Pamela Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Morelli, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Kumar, Vijay. University of Colorado; Estados Unidos Fil: Wempe, Michael F.. University of Colorado; Estados Unidos Fil: Cuello, A. C.. McGill University; Canadá Fil: Fernandez Megia, Eduardo. Universidad de Santiago de Compostela; España Fil: Bruno, Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; Argentina. Universidad Catolica de Cuyo. Facultad de Ciencias Medicas. Instituto de Investigacion En Ciencias Biomedicas.; Argentina
- Subjects :
- Apolipoprotein E
Polymers
DMHCA
General Physics and Astronomy
02 engineering and technology
Pharmacology
dendrimer
01 natural sciences
purl.org/becyt/ford/1 [https]
chemistry.chemical_compound
Mice
General Materials Science
Tissue Distribution
Cognitive decline
Liver X Receptors
Dendrimer
biology
General Engineering
Brain
polymeric micelle
Amyloid-Beta
021001 nanoscience & nanotechnology
amyloid-beta
medicine.anatomical_structure
ALZHEIMER'S DISEASE
0210 nano-technology
Alzheimer’s disease
liver X receptor
Amyloid beta
Central nervous system
Mice, Transgenic
010402 general chemistry
Blood–brain barrier
Partial agonist
Article
Alzheimer Disease
Polymeric micelle
medicine
Animals
Cognitive Dysfunction
Liver X receptor
purl.org/becyt/ford/1.6 [https]
Amyloid beta-Peptides
Cholesterol
0104 chemical sciences
Disease Models, Animal
chemistry
Drug delivery
drug delivery
biology.protein
Subjects
Details
- ISSN :
- 1936086X
- Volume :
- 15
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- ACS nano
- Accession number :
- edsair.doi.dedup.....0c743d07f2d0b50712468b3b569bdfc6