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

PROJECT SUMMARY
Currently, ~5.7 million Americans live with Alzheimer’s disease (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 the identification of
AD-risk patients and early intervention prior to disease onset. Accumulating data support that early events that
may contribute to AD-onset include the abnormal upregulation of reactive oxygen species (ROS) and
dysregulation of lipid metabolism. These features were seemingly disconnected until we recently discovered
that elevating ROS within neurons induces the formation of peroxidated lipids, which are transferred from the
neurons to surrounding glia. Within glia, these lipids form LD and are, presumably, resolved. Inhibiting this
process drives ROS-induced neurotoxicity. During chronic neuronal ROS, glia become overrun with LD and
die, leaving the neurons vulnerable. This pathway is conserved in flies and mice, with supportive human data.
Currently, we are uncovering the potential role of glial LD formation in AD. Preliminary data in Drosophila
demonstrate that genes defined as risk factors for AD by GWAS converge onto the glial LD formation pathway.
ABCA transporters, ABCA1 and ABCA7, are required in stressed neurons for glial LD formation, likely for the
export of peroxidated lipids. Further, four genes – LRP1, PICALM, CD2AP, and AP2A2 – are required in glia,
likely for the uptake of peroxidated lipids. We also found that the disease gene, Tau, is required within glia for
LD formation. Last, preliminary and published data support that disrupting glial LD formation may drive
extracellular Aβ42 accumulation, NFT formation, and disease. Overall, we hypothesize that glial LD formation
is an early event that attenuates elevated ROS in healthy brains and this process becomes prematurely
defective in AD. Building upon our current data, we will define potential contributions of glial LD formation
defects on ROS-induced neurodegeneration, insoluble Aβ42 buildup, and NFT formation. Aim 1 will investigate
AD-risk genes and AD-associated variants for involvement in glial LD formation during elevated ROS in
neurons using novel humanized fly models. Aim 2 will focus on Tau as a potential mediator of glial LD
formation in novel and established fly models, defining differing impacts of human Tau isoforms and mutations,
and assessing if defects in glial LD formation can contribute to the phosphorylation/ aggregation of Tau. Last,
Aim 3 will explore defined mechanisms from flies in mammalian systems. Initially, an established rat
neuron:glia co-culture model that can measure lipid transfer from stressed neurons to glia and their
accumulation into glial LD will be used to test if AD-risk genes and Tau can mediate this process. Further,
pathological studies will be performed on post-mortem AD tissue to determine correlations between LD
presence and disease features (e.g. Aβ42-plaques, NFT, disease severity, and presence of AD-risk variants).

Grant Number: 5R01AG073260-05
NIH Institute/Center: NIH
Principal Investigator: HUGO BELLEN