National Institute on Aging 5R01AG073260-05

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

This NIH-funded project investigates the role of glial lipid droplet formation in Alzheimer's disease (AD) pathology, focusing on oxidative stress and neurodegeneration mechanisms. It aims to identify how lipid metabolism and AD-risk genes contribute to disease onset and progression, potentially revealing new therapeutic targets.

Description

These studies will explore connections between Alzheimer’s disease (AD) and a novel, non-cell autonomous, neuroprotective pathway involving lipid droplet formation in glia due to neuronal stress. The identification of pathways that contribute to AD-onset is likely a key component in the development of a successful therapy. By taking a multidisciplinary approach, our work will define the impact of glial LD formation on disease-risk, onset, and progression while considering the role of genes that are potential therapeutic targets. Currently, ~5.7 million Americans live with AD, representing a significant burden on society and our healthcare system. Despite long-standing knowledge that AD involves the aberrant accumulation of Aβ42-plaques and neurofibrillary tangles (NFT; composed of hyperphosphorylated Tau), a successful treatment for AD has yet to be defined. Successful therapies will likely involve early identification of AD-risk patients and intervention prior to disease onset. Early events contributing to AD-onset include elevated reactive oxygen species (ROS) and dysregulation of lipid metabolism. Recent discoveries indicate that elevating ROS induces formation of peroxidated lipids transferred from neurons to glia, forming lipid droplets (LD). Disruption of this process leads to neurotoxicity, and glia overrun with LD die, leaving neurons vulnerable. This pathway is conserved across species, with supportive human data. Preliminary data in Drosophila show that AD risk genes converge onto the glial LD formation pathway, involving ABCA transporters (ABCA1, ABCA7), and other genes like LRP1, PICALM, CD2AP, and AP2A2. The disease gene Tau is also required within glia for LD formation. Disrupting glial LD formation may drive extracellular Aβ42 accumulation, NFT formation, and disease progression. The hypothesis is that glial LD formation is an early protective event that becomes defective in AD. Research aims include investigating AD-risk genes and variants involved in glial LD formation during elevated neuronal ROS using humanized fly models; studying Tau as a mediator of glial LD formation in fly models, assessing impacts of Tau isoforms and mutations, and their relation to Tau phosphorylation and aggregation; and translating findings to mammalian systems, including rat neuron-glia co-culture models to measure lipid transfer and accumulation, and analyzing post-mortem AD tissues for LD presence and disease features.

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