Molecular mechanisms of reelin/ApoE signaling and synaptic function according to APOE genotype

Abstract

The APOE4 allele (so-called µ4) is the strongest genetic risk for sporadic late-onset Alzheimer's disease (LOAD), and is associated with an increase in the levels of amyloid deposition and an early cognitive impairment. To understand the relation between APOE genotype and brain electrical activity, we developed a systematic review, which was recently submitted and is entitled "A systematic review on the association between Apolipoprotein-E genotype and P300 event-related potential". Results of this paper showed that APOE4 is related to increased P300 latency and its influence occur throughout the whole lifespan, ranging from the youth to the older people with dementia; however, studies did not investigate which molecular mechanisms would be responsible for the alterations in brain electrical activity of APOE4 carriers. The research group "Altered molecular mechanism in Alzheimer's disease and dementia", which is led by Prof. Dr. Javier Sáez-Valero from the Institute of Neurosciences in the Universidad Miguel Hernández is pioneer in investigating molecular mechanisms of synaptic dysfunction in AD through the reelin/ApoE signaling pathway investigation, and currently is studying this signaling in APOE genotype. Impaired reelin signaling is related to decreased synaptic plasticity and reduced brain network in AD, being ApoE an alternative ligand of the reelin receptors, thus regulating the signaling. The characterization and quantification of proteins implicated in the regulation of synaptic function, as reelin, ApoE and soluble fragments of the reelin/ApoE receptor 2 (ApoER2), as well as the amyloid precursor protein APP, could be a tool to evaluate the efficiency of reelin/ApoE signaling in the brain. Thus, the objective of this project is to study the reelin signaling mechanisms and synaptic functions according to APOE genotype. To this end during the internship abroad we will develop analyses of ApoE, reelin and intracellular ApoER2 and APP C-terminal fragments levels in cerebrospinal fluid (CSF) and brain extracts from AD and control participants carriers and non-carriers of APOE4. Furthermore, in ApoE-treated cells, the proteolytic processing of the APP (the precursor of A²), the dendritic spine density, and the affinities of ApoE isoforms for ApoER2 will be also analyzed. It is important to highlight that, in Brazil, it is not common to conduct studies with human brains, since we do not have large brain banks available. The results of this study will help to better understand the effects of APOE genotype on synaptic function, through an analysis of the molecular mechanisms involved in the reelin/ApoE signaling. (AU)