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Advanced Neurology Lipid droplets and neurodegenerative disorders

sequencing has identified “disease-associated microglia” cholesterol homeostasis. 40,41 The deficiency of ACAT1 in
(DAM) as a subset of the resident phagocytic microglia macrophages may reduce the responsiveness to cholesterol
population, which plays a protective role. According to loading and alleviate proinflammatory responses.
42
human genome-wide association studies (GWASs), DAM Furthermore, ablation of ACAT1 gene in triple transgenic
shows unique transcriptional profiles which are highly AD mice causes more reduction in full-length human
associated to AD and other NDDs. In response to damage- APPswe and attenuates cognitive impairments, which
36
associated molecular patterns, DAM produces ROS from emerge as potential target for AD therapy. 43
damaged cells, leading to lipid peroxidation, protein Another important role of LDs during brain
oxidation, and mitochondrial dysfunction. Recent studies development is to buffer the histone levels of transcription
37
have identified another subgroup of microglia named in neural stem cells. Various epigenetic elements, including
“LDAM” in both aging mouse and human brain samples, histone deacetylases (HDACs), have been found to
which exhibit impaired phagocytosis, increased oxidative coordinate with stem cell pluripotency, self-renewal,
production of ROS, and superabundant proinflammatory neuronal proliferation, and differentiation to neural stem
cytokines. 38
cells through the manner of chromatin remodeling and
5. LDs in brain development and aging epigenetic modifications. Among HDACs, the HDAC1,
HDAC3, HDAC5, and HDAC7 are highly expressed
As the second most lipid-rich organ, the brain is abundant in neural stem cells. Plethoric histones H2A, H2B,
44
with phospholipids and neutral lipids serving as energy and H2Av are toxic for brain development. Although
supply. The lipid molecules comprise nearly a half of the molecular mechanism of how LDs regulate the
the dry weight of brain. Under normal physiological histone storage remains unclear, in Drosophila embryos,
conditions, the presence of LDs is essential for the brain concurrent accumulation of histones and LDs happens
development. Neurons and neuroglia are derived from during oogenesis. 45,46 The histone-docking anchor Jabba
neural stem cells and progenitor cells, undergoing three can directly interact with histones and recruit them to LDs.
types of division, including symmetric proliferative Jabba can bind to LDs-localized H2A, H2B, and H2Av to
division, symmetric neurogenic division, and asymmetric stabilize these histones for chromatin assembly in the early
neurogenic division. During brain development, LDs Drosophila embryogenesis. 46
39
protect the neural stem cells from oxidative stress.
Hypoxia is a modulator of neuronal proliferation and Brain aging is a comprehensive process with an
enhances cellular proliferative capacity. The neural stem accumulation of unpredictable programmed and random
cells residing in unique hypoxic microenvironment named damage to the neuronal cells. The hallmarks in the brain
niches, can activate hypoxia-inducible factor and increase during aging are described as: intracellular accumulation
the production of ROS, and then in feedback trigger LDs of oxidative stress, damaged proteins, nucleic acids and
formation and metabolic programing in neuron and lipids, and mitochondrial dysfunction. It has been found
neuroglia. The LDs are mostly distributed around the that LDs of microglia accumulate in 20-month-old mice
3,32
niche glia, which acts as a protective event to limit ROS brain during aging, showing abundant BODIPY+ positive
production and inhibit the oxidation of polyunsaturated signals. Similarly, additional analysis showed that there were
fatty acids during the development of neural stem cells. 3 more PLIN2+ and Iba1+ microglia in aging postmortem
brain tissues than in young individual. In 18-month-old
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Cholesterol stored in LDs is especially enriched in
synaptic and myelin membranes. Cholesterol is closely mice, there was an increased density of LDs in cerebral Oil
Red O-positive lipid-laden cells (LLCs), which appear to
involved in brain myelination, neuronal differentiation, distribute in the cortex and striatum region. It has been
synaptogenesis, and neurotransmission. The demands of found that LCCs are also spread out in the pia mater and
cholesterol biosynthesis in CNS vary with development
periods. During the brain development stage, cholesterol is blood vessels in the aging brain. This suggests that LLC may
highly demanded to build up the major portion of myelin experience the migration from adjacent connective tissue
sheaths for rapid saltatory neuron-to-neuron conduction. and perivascular region to neural parenchyma during the
aging process.
47
In adult brains of rodent animals, there is around 80% of
cholesterol in myelin. Cholesterol and myelin membrane The novel state of microglia, LDAM, has been defined as
contact and restrain each other. The acyl-coenzyme A: a hallmark of brain aging or neurodegeneration. Impaired
cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), phagocytic activity has been determined in LDAM
also termed as sterol O-acyltransferases, can convert excess compared to LDs- microglia in aging brain. It is unclear
fatty acid to cholesteryl esters and lead to cholesterol ester whether defective phagocytosis is a cause or consequence
storage in LDs, thus playing essential roles in neuronal of LDs. In vitro studies showed that pharmacological

Volume 4 Issue 2 (2025) 5 doi: 10.36922/an.5060