Targeting amyloid-beta, the key protein in Alzheimer disease

CiQUS researchers design a new treatment conducted in mice to prevent memory deterioration without undesirable side effects. The results of this preclinical study has now been published in the renowned journal ACS Nano(link is external).

Amyloid-beta accumulation in the brain is a common prelude of Alzheimer´s disease. Before the first symptoms appear, these deposits turn into toxic plaques between neurons that are responsible for progressive cognitive decline. By designing a new polymer, scientists at Center for Research in Biological Chemistry and Molecular Materials (CiQUS) in collaboration with researchers from Universidad Católica de Cuyo (Argentina) have been able to reduce the levels of this peptide without side effects. In preclinical studies and administered in the early stages of the disease, this treatment has contributed to prevent memory deterioration.

The main contribution to amyloid-beta drainage from the brain comes from apolipoprotein E (ApoE). On the other hand, DMHCA represents an excellent therapeutic candidate for Alzheimer. With a cholesterol-like structure, this substance activates the receptors to induce ApoE expression without affecting cholesterol and triglyceride levels. The problem: its low solubility and inability to cross the blood brain barrier, a highly selective membrane. “We hypothesized that a controlled incorporation of DMHCA into a polymeric scaffold could afford an amphiphilic copolymer prone to form micelles, similar to soap” explains Eduardo Fernández Megía, CiQUS principal investigator and co-author of the study. Previously, his lab had successfully participated in the development of suitable nanoparticles to cross the blood brain barrier in order to prevent cerebral stroke. Based on this hypothesis, the researchers´ approach was “to develop polymeric micelles from dendritic copolymers with covalent incorporation of DMHCA, not by simple encapsulation” reveals Fernández Megía.

Studies in primary cell cultures showed that the micelles were able to internalize neurons and astrocytes. Later, the Argentinian team intranasally administered the micelles to transgenic mice finding that ApoE production increased while reducing amyloid-beta deposition, preventing cognitive deficits without compromising cholesterol and triglyceride blood levels. The authors believe these results, now published in the renowned journal ACS Nano(link is external), enable further clinical applications of DMHCA delivery systems to fight Alzheimer´s disease.

Reference

Liver X Receptor Activation with an Intranasal Polymer Therapeutic Prevents Cognitive Decline without Altering Lipid Levels. María Eugenia Navas Guimaraes, Roi Lopez-Blanco, Juan Correa, Marcos Fernandez-Villamarin, María Beatriz Bistué, Pamela Martino-Adami, Laura Morelli, Vijay Kumar, Michael F. Wempe, A. C. Cuello, Eduardo Fernandez-Megia, and Martin A. Bruno. ACS Nano 2021 15 (3), 4678-4687

DOI: 10.1021/acsnano.0c09159