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Advanced Neurology Lipid droplets and neurodegenerative disorders

neuroglia. When under metabolically stressed conditions, metabolism is pivotal to maintain the neuronal activity
increased ROS can drive de novo synthesis of fatty acids in after depletion of energy substrates. In astrocyte, glucose
neurons, leading to the accumulation of lipotoxicity. Due can be synthesized by glycolysis or glycogen shunt to
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to the low capacity for the formation of LDs and fatty acid pyruvate, and lately degraded to lactate, which is then
metabolism, hyperactive neurons would deliver toxic fatty transported into neurons and oxidatively metabolized as
acid to neighboring neuroglia. emergency fuels. 16,30 In addition, glycogen in astrocytes
Microglia, the resident immune cells within CNS, can also be converted to glutamine, which is a precursor of
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are associated with the regulation of neuroinflammation neurotransmitter glutamate. In response to hypoxia and
and oxidative stress to maintain neuronal homeostasis. metabolic stress, astrocytes prefer anaerobic metabolism of
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glycolytic production of L-lactate. L-lactate is used for de
There are several ways of LDs formation in microglia,
including endocytosis of dead cells via triggering novo fatty acid synthesis and ATP production in neurons
receptor expressed on myeloid cells 2 (TREM2)-mediated under oxidative stress condition. Excess L-lactate could
myelin phagocytosis, oxidized-phospholipid-containing trigger LDs accumulation in astrocytes, which leads to
pathogenesis of NDDs.
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particles, and neuronal-derived LDs. 1,21-24 Microglia are
highly sensitive to environmental changes, including The intercellular crosstalk of lipid metabolism in LDs
increased ROS production, lipotoxicity, inflammation, across neurons and neuroglia plays essential roles for brain
and intracellular stress. Under stress conditions or during function, including metabolic homeostasis, synaptogenesis,
the aging process, “resting” microglia transform into the and neurotransmission. Further investigations are required
activated form. A novel subtype of activated microglia with to elucidate how trafficking pathway of LDs integrates
accumulated LDs, termed as “lipid-droplet-accumulating- within various cell types, and how they might evolve in the
microglia” (LDAM), exhibits a unique transcriptional pathogenesis of aging-associated NDDs.
profile, which is linked to dysregulation of phagocytosis,
production of ROS, neuroinflammation, and decreased 4. LDs in neuroinflammation
cholesterol efflux. LDAM are abundant in the aging The brain is highly susceptible to the oxidative stress.
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brain, which can either prevent from or contribute to Oxidative stress is considered a key modulator of various
the neuroinflammation and NNDs. Recently, it has been NNDs during the aging process. The excess level of ROS is
reported that LDAM with ApoE4 genotype promotes the prone to induce oxidative stress and initiates the generation
microglial status to a more maladaptive and damaging of multiple inflammatory cytokines. It is important to
states, which is more likely contribute to Alzheimer’s maintain a low level of ROS for intracellular homeostasis
disease (AD) pathogenesis. 26-28 Future studies targeting the in the brain. When neuronal cells are exposed to high
harmful roles of LDAM in AD might better uncover the concentration of ROS for a long-term, various cellular
intricate regulatory mechanism of NDDs. macromolecules, including DNA, RNA, proteins, and

Astrocytes are the predominant cell type accounting for lipids, may suffer from the ROS, in turn cause neuronal
around 40% in CNS, which are associated with a plethora apoptosis and death. The excessive accumulation of ROS
of functions, including the formation of blood-brain and lipotoxicity can result in neuroinflammation and even
barrier, synaptogenesis, regulation of neurotransmission, NNDs in brain. LDs formation can buffer cellular stress
and metabolic regulation. Astrocytes also serve as an and restrict the levels of ROS. Lipopolysaccharide, which
important role of LDs formation and metabolism. can initiate a cascade of proinflammatory mediators that
In fact, neurons have limited capacity for LDs and are necessary to activate immune response, induces LDs
glycogen storage, so that energy is quickly consumed. formation through Toll-like receptor 4 (TLR4)-depended
Astrocytes can synthesize lipids, including fatty acids and response pathway in macrophages. 33,34 Activation of
cholesterol, through de novo way, which play important TLR4 triggers the downstream signal pathway, including
roles in neuronal metabolisms. Fatty acids released from mitogen-activated protein kinases cascade, nuclear factor
membranes of astrocytes can shuttle into neurons via kappa-B (NF-κB) cascade, inhibitor of NF-κB cascade and
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endocytosis of fatty acids transporters or ApoE particles. c-Jun N-terminal kinase signaling pathway, which then
These fatty acids are mostly applied to the building sources induces the activation of transcription complex activator
of membrane for axonal growth and CNS myelination. protein-1 to promote the expression of proinflammatory
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Cholesterol is primarily synthesized in astrocytes, and cytokines.
then secreted as ApoE-containing particles, which can In the brain of inflammation, microglia suffer from the
be endocytosed by neurons through LDL receptor and oxidative stress and ROS. Following the technologically-
lipoprotein receptor-related protein. Astrocytic glycogen advanced genomic research, single-cell transcriptome

Volume 4 Issue 2 (2025) 4 doi: 10.36922/an.5060