Critical Review of the Alzheimer's Disease Non-Transgenic Models: Can They Contribute to Disease Treatment?

Alzheimer's disease (AD) is a growing neurodegenerative disease without effective treatments or therapies. Despite the use of different approaches and an extensive variety of genetic amyloid based models, therapeutic strategies remain elusive. AD is characterized by three main pathological hallmarks that include amyloid-ß plaques, neurofibrillary tangles, and neuroinflammatory processes; however, many other pathological mechanisms have been described in the literature. Nonetheless, the study of the disease and the screening of potential therapies is heavily weighted toward the study of amyloid-ß transgenic models. Non-transgenic models may aid in the study of complex pathological states and provide a suitable complementary alternative to evaluating therapeutic biomedical and intervention strategies. In this review, we evaluate the literature on non-transgenic alternatives, focusing on the use of these models for testing therapeutic strategies, and assess their contribution to understanding AD. This review aims to underscore the need for a shift in preclinical research on intervention strategies for AD from amyloid-based to alternative, complementary non-amyloid approaches.

Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer's Disease.

Neuroinflammation is one of the hallmarks of Alzheimer's disease pathology. Amyloid ß has a central role in microglia activation and the subsequent secretion of inflammatory mediators that are associated with neuronal toxicity. The recognition of amyloid ß by microglia depends on the expression of several receptors implicated in the clearance of amyloid and in cell activation. CD36 receptor expressed on microglia interacts with fibrils of amyloid inducing the release of proinflammatory cytokines and amyloid internalization. The interruption of the interaction CD36-amyloid ß compromises the activation of microglia cells. We have developed and validated a new colorimetric assay to identify potential inhibitors of the binding of amyloid ß to CD36. We have found seven molecules, structural analogues of the Trichodermamide family of natural products that interfere with the interaction CD36-amyloid ß. By combining molecular docking and dynamics simulations, we suggested the second fatty acids binding site within the large luminal hydrophobic tunnel, present in the extracellular domain of CD36, as the binding pocket of these compounds. Free energy calculations predicted the nonpolar component as the driving force for the binding of these inhibitors. These molecules also inhibited the production of TNF-α, IL-6, and IL-1ß by peritoneal macrophages stimulated with fibrils of amyloid ß. This work serves as a platform for the identification of new potential anti-inflammatory agents for the treatment of Alzheimer's disease.

Uprolides N, O and P from the Panamanian Octocoral Eunicea succinea.

Three new diterpenes, uprolide N (1), uprolide O (2), uprolide P (3) and a known one, dolabellane (4), were isolated from the CH2Cl2-MeOH extract of the gorgonian octocoral Eunicea succinea, collected from Bocas del Toro, on the Caribbean coast of Panama. Their structures were determined using spectroscopic analyses, including 1D and 2D NMR and high-resolution mass spectrometry (HRMS) together with molecular modeling studies. Compounds 1-3 displayed anti-inflammatory properties by inhibiting production of Tumor Necrosis Factor (TNF) and Interleukin (IL)-6 induced by lipopolysaccharide (LPS) in murine macrophages.