IMPACTS OF GLIAL LIPID DROPLETS ON OXIDATIVE STRESS AND NEURODEGENERATION IN ALZHEIMER'S DISEASE

Baylor College Of Medicine, Houston TX

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Abstract

Summary – Administrative Supplement Funded Parent Award (R01 AG073260-02; project ends on 05/31/2026) The parent R01 is focused on studying the impacts of glial lipid droplets on oxidative stress and neurodegeneration in Alzheimer's disease (AD). It takes an interdisciplinary approach to further probe connections between age-related ROS and lipid dysregulation, AD risk factors, Aβ42 accumulation and Tau in the context of glial lipid droplet formation. As AD is an age-associated disease, there are likely numerous aging-related features that impact disease onset and progression, including the dysregulation of lipids and aberrant upregulation of ROS. The parent grant focuses on how these features impact neuron-glial interactions and AD-associated pathologies, Aβ42 and Tau, in the nervous system. However, the dysregulation of lipids and ROS is likely to impact multiple tissues. It is notable that lipid and ROS dysregulation is associated with numerous age- associated diseases impacting the periphery, including cardiovascular disease, obesity, and intestinal dysplasia. Fittingly, there is growing interest in understanding the interplay between AD and the periphery in the context of aging. As such, AD has been connected to disruptions in the gut microbiome, respiratory system, cardiovascular function, and hormone homeostasis, supporting that peripheral tissues are also involved in disease. However, a causal relationship between AD progression and peripheral dysregulation is not well established. Here, we propose to systematically investigate how AD progression impacts an entire organism at cellular resolution using Drosophila and a cell atlas approach. Recent advances in single-cell RNA sequencing (scRNA-seq) technologies and the establishment of the Fly Cell Atlas (FCA) (Fig. 1A) offer an unprecedented opportunity to explore this potential relationship at the cellular level. The FCA is a single-nucleus transcriptomic dataset in which over 250 cell types were identified in the whole adult fly. By combining snRNA-seq with lipidomics we aim to highlight cellular mechanisms within the periphery that are impacted by toxic Aβ42 or Tau during the aging process. Drosophila is an ideal model system for such investigations as this simple organism, a rapid lifespan and less redundancies in terms of genes that perform the same or similar functions. This work targets to characterize how AD progression affects different cell types across the whole organism and to define interactions with age-associated lipid dysregulation. Based on the criteria for Administrative Supplements, we believe that our proposal fits very well for the criteria of availability of a new technology (Li et al., 2022). Further, this supplement is a natural extension of our funded studies on non-cell autonomous mechanisms and lipid dysregulation that contribute to AD. 1