Investigating cell-type specific convergence of APOE and ABCA7 lipid dysregulation in Alzheimer’s disease

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Project Summary/Abstract Alzheimer’s disease (AD) is a progressive and fatal disorder characterized by memory loss and cognitive decline. It accounts for 60-80% of dementia cases and affects more than 20% of people over age 75. Several genetic risk factors have been identified, yet mechanisms linking them to AD onset, progression, or severity are still largely unknown. Therapeutic interventions, which have focused on improving pathological hallmarks of AD such as amyloid accumulation, have had only limited success, suggesting the need to identify new approaches. Lipid dysregulation has long been known to be important in AD, and damage to the lipid-rich myelin in white brain matter is emerging as a key pathology, pointing to the importance of lipid-related pathways as potential drug targets. However, studies of the mechanisms underlying lipid dysregulation in AD have been limited. This project seeks to identify commonalities in how AD risk variants in two different lipid-associated proteins, the lipid carrier ApoE and the trans- membrane lipid transporter ABCA7, lead to lipid dysregulation in oligodendroglia, the cells responsible for creating and maintaining the myelin sheath around neuronal axons. Single-cell RNAseq data from post-mortem brain samples will be used to identify transcriptional signatures that are present both in samples with the APOE4 variant and in samples with loss-of-function (LoF) variants in ABCA7 to reveal key lipid-related pathways that are perturbed by risk variants in either protein. The molecular and functional consequences of these pathway perturbations will then be explored in-depth in models based on induced pluripotent stem cells (iPSC) containing these risk variants. Co-culture systems of iPSC-derived oligodendrolia (iOG) and neurons (iN) have been shown to achieve axonal myelination and thus represent a fully tractable and modular model of neuron-oligodendrocyte interaction and oligodendrocyte functionality. The specific aims are (1) to characterize the lipid dysregulation and its underlying causes in iOG bearing the APOE4 variant or LoF variants in ABCA7; (2) to characterize the impact of the APOE4 variant or LoF variants in ABCA7 on myelination in iOG-iN co-cultures and to determine if the variant effects can be rescued by pharmacological intervention; in addition, targeted disruption of individual genes within the dysregulated pathways will be used to identify key regulatory genes involved in the variant effects; (3) to investigate if the transcriptional signatures found in samples with APOE4 or LoF variants in ABCA7 are also present in AD post- mortem brain samples that are non-carriers for APOE4 or ABCA7 LoF or bear other risk variants implicated in lipid metabolism, potentially identifying a sub-category of AD.