In vitro modeling of the blood-brain barrier for studies of late-onset Alzheimer's Disease

• Grant number: 23/09081-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2023
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Marimélia Aparecida Porcionatto
• Grantee: Márcio Henrique Mello da Luz
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 18/12605-8 - Development of brain-on-a-chip microplataforms for in vitro modeling of the central nervous system, AP.TEM

Abstract

The blood-brain barrier (BBB) is a highly specialized structure composed of endothelial cells, pericytes, and astrocytes and plays crucial roles in the physiology of the central nervous system (CNS). The BBB acts through mechanisms of selective permeability, preventing the entry into the CNS of potentially neurotoxic agents and allowing the exit of molecules resulting from cellular metabolism, such as beta-amyloid (Ab) peptides, transported by receptors of the LDL receptor family. Amyloid beta peptide (AbO) oligomer accumulation is one of the primary markers of Alzheimer's disease (AD), and BBB dysfunction that leads to decreased Ab clearance has been linked to disease development and progression. LRP1 (low-density lipoprotein receptor-related protein-1) and RAGE (receptor for advanced glycation end products) receptors were identified as responsible for transporting Ab from the brain to the blood and from the blood to the brain, respectively. RAGEs have been suggested as a potential link between type 2 diabetes and sporadic or late-onset AD and other neurodegenerative diseases. Biochemical and cellular alterations observed in sporadic AD can be explained by the activation of RAGEs by advanced glycation products (AGE - advanced glycation products), such as increased production of reactive oxygen species (ROS) by activation of microglia and neuronal death. Models of sporadic AD are still scarce, and most studies are based on animal models of the familial form of the disease based on mutations found in humans, representing only about 5% of cases. In this context, new models of the sporadic form have been developed, including the intracerebral injection of the Ab25-35 peptide to mimic the acute phase of the disease, represented by the beginning of AbO accumulation. Recent studies using an animal model of sporadic AD suggest that environmental risk factors, such as a diet high in fat and sugar, may lead to the onset of the disease depending on the presence of genetic risk factors, such as APOE4 expression. In vitro, models that mimic sporadic AD are even more scarce, and brain organoids have been identified as promising models for studying the cellular and molecular mechanisms of AD pathology. However, because it is a non-vascularized structure, organoids do not have BBB, which should be incorporated into models to understand the pathophysiology of the disease. Due to its complexity, in vitro models of the BBB are still under development. In vitro, models that reproduce the appearance and effect of sporadic AD have great appeal to be used to search for early biomarkers of the disease and in tests of new drugs to treat the condition. The main objective of this project is to validate an in vitro model of BBB in a microfluidic device by evaluating the participation of LRP1 and RAGE receptors in the transport of Ab from the "blood" compartment to the "brain parenchyma" compartment and vice versa. (AU)