Page 12 - AN-4-2

Advanced Neurology Lipid droplets and neurodegenerative disorders

inhibition of LDs production with Triacsin C, an inhibitor are linked to have about 9- to 15-fold increased risk of
of long-chain acyl-CoA synthetase to inhibit endogenous AD, 58,59 which have more severe AD pathologies, including
synthesis of glycerolipids, can promote phagocytosis and increased Aβ accumulation and neurofibrillary tangles,
inhibit ROS formation in BV2 cells. Treating BV2 cells and elevated levels of inflammatory cytokines. Given ApoE
25
with proinflammatory endotoxin lipopolysaccharide is important for lipid transport and metabolism in neuron
increased phagocytic activity and promoted LDs and neuroglia, it is not surprising that ApoE can alter the
formation. Moreover, culturing BV2 cells with 5% plasma LDs accumulation in the AD brain. ApoE serves distinct
from 18-month-old aged mice can induce a higher density roles in the regulation of lipid transport within different
of LDs. Given these studies, there shows a close interplay neuronal cells. Astrocytes are the initial site of oxidation
48
between aging and LDs. of fatty acid and are thought to be major sites expressing
ApoE. Astrocytes are responsible for transportation of fatty
6. LDs in AD acids away from hyperexcitable neuronal cells and storing

In recent years, numerous studies have shown the them in LDs to provide energy to brain during starvation.
connections between LDs accumulation and NDDs, such ApoE4 in astrocytes can promote the expression of PLIN-2,
60
as AD, Parkinson’s disease (PD), and amyotrophic lateral whose levels are highly correlated with LDs abundance,
sclerosis. AD is the most common type of dementia, and inhibit oxidation of fatty acid, and increase the volume
which is characterized by extracellular deposition of but decrease size of LDs. It has been reported that ApoE
β-amyloid (Aβ) plaques, intracellular neurofibrillary shows binding affinity for complement component 1q
tangles composed of hyperphosphorylated tau, and (C1q) on LDs in choroid plexus niche. C1q is the initial
neuron loss in the brain. In recent studies, more other protein of the classic complement cascade of the immune
61
pathologies have been revealed in the AD process, such system. It has been suggested that ApoE may regulate the
as dysregulation of glucose metabolism, oxidative stress- complement pathway within the choroid plexus during the
induced neuroinflammation, mitochondrial dysfunction, progression of AD.
and abnormal lipid metabolism. 49,50 In 1907, when The neurons also express ApoE but only under
Alois Alzheimer first described the AD case of Auguste the circumstance of oxidative stress to facilitate their
Deter, he also noted the presence of “adipose saccules” lipid transfer and fatty acid clearance. The neurons
or LDs inclusions in microglia. Until recent years, the also participate in the regulation of LDs metabolism
51
phenomenon of increased lipid accumulation in AD through the same manner. A recent single-nucleus RNA
has been widely noticed. In LDs, cholesterol can be sequencing has found that acyl-CoA synthetase long-
52
converted to cholesteryl esters by ACAT during normal chain family member 1, a key enzyme of LDs biogenesis,
LDs biogenesis. Excess cholesterol and cholesteryl esters is abundant in the AD microglia with ApoE4 genotype.
26
within LDs regulate Aβ and tau pathology independently. This finding indicates that damaged LDAMs could affect
Intracellular cholesterol accumulation impairs mitophagy the AD pathogenesis in an ApoE4-dependent way. In
by disrupting optineurin recruitment and lysosomal addition, there is a TREM2-APOE pathway that can induce
clearance, leading to decreased Aβ clearance. This blockage microglia state switch from homeostatic to detrimental in
of autophagic flux also leads to the increased HDAC6+ AD. TREM2, a transmembrane receptor expressed in
62
aggregates in AD brains samples, which have been reported microglia, can be activated by multiple ligands including
to be increased by 90% in AD hippocampus. As for lipids. TREM2 might promote the buildup of LDs by an
53
tau-related pathology, inhibition of neuronal cholesterol ApoE4-dependent regulation on lipid metabolism, and
esterification through deletion of ACAT1 gene may induce thus affect the AD pathogenesis. 63,64
tau degradation by regulation of ubiquitin-proteasome
levels in APP- and Aβ-independent manner. 54 7. LDs in PD
ApoE is responsible for lipid metabolism and cholesterol PD, the second most common NDD after AD, is
homeostasis in CNS. The human ApoE gene has three characterized by the loss of dopaminergic neurons in
polymorphic forms of alleles, including ApoE ɛ2, ɛ3, and the substantia nigra and intracellular accumulation of
ɛ4, which are translated into three isoforms of ApoE2, α-synuclein. The disturbance in lipid metabolism has
ApoE3, and ApoE4. The different ApoE isoforms have also been reported in PD. According to GWASs, it has
55
different binding capacity to interact with lipids, receptors, been validated that a lipid-associated pathway leads to PD
and Aβ. The ɛ4 allele of ApoE has been identified as the development. The vesicle trafficking and lipid homeostasis-
strongest genetic risk factor to develop AD, while ɛ2 and ɛ3 associated genes are regarded risk factors of PD.
alleles are protective roles in brain. 56,57 The ApoE4 carriers α-synuclein is a lipid-binding protein that directly binds
bearing either in a heterozygous or homozygous genotype with fatty acids and phospholipids under physiological

Volume 4 Issue 2 (2025) 6 doi: 10.36922/an.5060