Scholarship 24/04078-9 - Barreira hematoencefálica, Bioimpressão - BV FAPESP
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Prohibitins in sporadic Alzheimer's disease: function and potential drug target

Grant number: 24/04078-9
Support Opportunities:Scholarships in Brazil - Doctorate
Start date until: December 01, 2024
End date until: August 31, 2028
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Marimélia Aparecida Porcionatto
Grantee:Tamirez Villas Boas Petrucci
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

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a gradual decline in memory and cognition, among other clinical hallmarks. The brain of an AD patient presents abnormal beta-amyloid (Ab) deposition in the extracellular matrix and intraneuronal neurofibrillary tangles. Familial AD (FAD) is genetically inherited and less frequent than sporadic AD (SAD), which comprises more than 90% of all cases. There are an estimated 50 million individuals with AD dementia globally. These epidemiologic predictions became a challenge for discovering new drugs to prevent the onset, delay progression, or improve symptoms. The recently approved therapies (aducanumab and lecanemab) provide relatively limited treatment possibilities (e.g., early AD) for the large and growing AD population. Recent studies have emphasized the neuroprotective potential of prohibitin (PHB) and PHB ligands. Based on data from the literature that showed PHBs have a neuroprotective effect on experimental traumatic brain injury and stroke, we hypothesize that PHB ligands may inhibit apoptosis of neurons exposed to Ab oligomers (AbO), increasing cell viability and reducing neuroinflammation and oxidative stress. PHB ligands such as flavaglines and their synthetic derivatives have been shown to exert neuroprotection through decreasing apoptosis and oxidative stress. Based on these, we aim to investigate the participation of PHBs in the development and progression of SAD and its potential as a drug target. We will use two in vitro models to achieve this goal: i) 3D bioprinted models of neurogenic niches and ii) the blood-brain barrier and neurovascular unit (BBB/NVU) models. In both models, we will mimic SAD by adding AbO to the bioink composition of the neurogenic niche model and the "brain side" of the BBB/NVU model. In this project, we will treat cells in the 3D bioprinted neurogenic niches and BBB/NVU with flavagline synthetic derivatives and evaluate cell viability, cell differentiation, reactive astrocyte activation, and oxidative stress. We expect to identify if PHBs play a role in the development and progression of SAD and if they could be used as a target for the development of novel drugs to treat AD.

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