Deciphering the Regulation and Expression of APOE in Alzheimer's Disease
MentorMina Ryten , MD, PhD
This goal of this project is to unravel the complete landscape of APOE transcripts to better understand the regulation APOE function and its involvement in Alzheimer’s disease. In aim 1 I will use targeted long-read RNA sequencing to identify APOE transcripts in brain regions analysed in Braak and Braak staging and Aß progression from patients with Alzheimer's disease and controls. In aim 2 I will quantify the transcript expression and perform spatial transcriptomic analyses to map where transcripts of interest are expressed. In aim 3 I will leverage publicly available and previously generated datasets to assess clinical correlations with specific APOE transcript usage and whether genetic variability regulates the inclusion of certain transcripts.
This project involves a recently developed, yet to be published, long-read RNA sequencing approach which can target any candidate gene and simultaneously multiplex samples. The result is full-length transcript sequences from which a complete understanding of splicing and APOE gene structure can be achieved. Additionally, paired with spatial transcriptomics, in brain samples from patients with Alzheimer’s disease, this will give us an understanding of APOE in the Alzheimer’s brain previously not achieved.A complete annotation of APOE gene structure and transcript diversity will let us better understand the mechanism of pathogenesis and to more comprehensively ascertain the Alzheimer’s disease risk associated with the APOE locus. This will also offer the potential to target specific disease relevant transcripts by means of antisense oligonucleotide technologies. Additionally, understanding how the quantitative regulation of certain APOE transcript occurs and where they are expressed will undoubtedly lead to the development of novel models to study the disease.