Investigating the physiological function of Alzheimer’s disease risk gene Abca7 in the central nervous system

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder, and there is currently no cure or preventative treatment. Therefore, understanding what makes certain people more susceptible to AD is critical to developing effective therapeutic strategies. Large-scale genome-wide studies have identified several risk genes for AD, opening a new era of mechanistic studies of AD pathogenesis. One key candidate that increases the risk of AD, especially in African American and Non-White Hispanic populations, is ATP-binding cassette transporter A7 (Abca7). Early in the disease pathogenesis, AD patients who harbor mutations in Abca7 have been shown to have very robust β-amyloid deposition and exhibit impairments in multiple cognitive domains; yet, how Abca7 mutations contribute to increased AD risk remains elusive because its normal role in the central nervous system (CNS) is poorly understood. As this is a widely unexplored research area, the goal of this thesis is to explore the normal function of Abca7 in the intact adult brain, which may provide crucial knowledge to understand its role in AD. I developed several mouse lines for studying Abca7 in vivo (Chapter 1), which will become available to the scientific community: Abca7-HA reporter, null Abca7-knockout (KO), and a floxed Abca7 mouse strains. Extending this work using my newly-generated Abca7-KO line, I present the first lines of evidence for (1) the spatiotemporal regulation and subcellular localization of the Abca7 protein in vivo and (2) the identification of gene and gene pathways in which Abca7 is involved (Chapters 2 and 3). Abca7 is expressed throughout neurodevelopment into adulthood and is ubiquitously expressed and localizes to membranes and synaptic membranes in the intact postnatal brain (Chapter 2). Most notably, Abca7 is important for GABAergic interneuron cellular pathways in the thalamus. Lacking Abca7 reduces the expression of several genes related to GABA synthesis, GABAergic synaptic vesicle protein levels, and aberrant anxiety-related behaviors in young and aged mice (Chapter 3). As the closest homologous protein of Abca7 is Abca1, a key cholesterol and lipid transporter in the body, I also investigated the potential role of Abca7 in neuro-lipid processing in Chapter 4. I did not identify differentially expressed lipid species in the presence versus absence of Abca7 in both young and aged brains. Taken together, this thesis work is the first to provide the groundwork for understanding the role of Abca7 in the normal brain, which will help guide future studies of its link to increased AD risk and pathogenesis.