Efecto de Contilisant en modelo murino doble transgénico para la Enfermedad de Alzheimer

Alzheimer's Disease (AD) is a progressive neurological disorder characterized by cognitive impairment (memory, speech, mental alertness) resulting from synaptic and neuronal loss. Multiple theories have been postulated about its aetiology. However, none of them explain the origin of the histopathological features: plaques formed by beta-amyloid (Aβ) peptides and aggregates of hyperphosphorylated TAU protein (p-Tau) in neurofibrillary tangles (NFT). It is a disease that occurs mainly in elderly, over 65 years old, although several associated risk factors have been defined, including genetics. There are 1% of Familiar Alzheimer's Disease (FAD) cases. Thanks to this type, the genes involved in the pathology have been discovered. For example, the gene that codes for Amyloid Precursor Protein (APP) or the gene that codes for Presenilins (PS1 and PS2). With the increase in life expectancy, the number of people suffering from AD is increasing every day. One-target one-compound drugs are not effective because the multifactorial character of AD escapes their palliative effects. However, the new Multi-Target Small Molecules (MTSM) trend aims to interfere with the pathology progression. Contilisant is a drug that belongs to this strategy. It is a molecule that evolved from ASS234, an inhibitor of Acetylcholinesterase (AChE), Monoamine Oxidase Enzymes (MAO), and Histamine 3 Receptors (H3R). In addition to radicals against these targets, different derivatives are being designed as an antagonist of Sigma 1 Receptors (S1R) and Serotonin 5-HT6 Receptors (5-HT6R) and inhibitors of Histone Deacetylase Enzymes (HDAC). Chemical synthesis, in silico, and in vitro analysis resulted in the MC911 derivative. In this research, the effect of MC911 was evaluated during two months of treatment in APPswe/PS1ΔE9 double transgenic mice models. All animals were sacrificed at five-month of age. Thioflavin-S staining was used to study Aβ load. Results did not lead to a significant reduction in the number of plaques in treated individuals compared to controls. The unusual expression of aggregates in one of the individuals deflected the trend. The experiment will be extended by increasing the number of subjects. In addition, immunohistochemical techniques using Glial Fibrillary Acidic Protein (GFAP) have been performed to determine astrocyte expression. These cells play an essential role in brain homeostasis and Aβ clearance. Fluorescence images show a decrease in the number of astrocytes for the treated individual compared to the control. Despite this, the efficacy of this more fibrillar morphology population cannot be determined. Finally, histochemical techniques with biotinylated lectin were carried out to analyse the vasculature. Their relationship between vasculature and astrocytes, the blood-brain barrier (BBB), and the drainage of aggregates are of great interest in the histological context. Fluorescence xii imaging shows increased branching and in calibre of large vessels in the treated individual compared to the control. The vasculature may spread to more tissue pathological area thus minimizing the accumulation of Aβ plaques