Review
Influential role of 7-Ketocholesterol in the progression of Alzheimer’s disease

https://doi.org/10.1016/j.prostaglandins.2021.106582Get rights and content

Highlights

  • 7-Ketocholesterol (7-KCH) involved in Alzheimer’s disease pathogenesis.

  • Intracellular proteostasis is necessary for neuronal functions.

  • 7-KCH affects the functions of cell organelles in neurons through lipid accumulation.

  • 7-KCH enhances the deposition of toxic aggregates as a consequence of dysfunctional organelles.

  • Biomolecules from different sources can prevent 7-KCH induced neuronal cell death.

Abstract

Millions of people are affected by neurodegenerative diseases worldwide. They occur due to the loss of brain functions or peripheral nervous system dysfunction. If untreated, prolonged condition ultimately leads to death. Mostly they are associated with stress, altered cholesterol metabolism, inflammation and organelle dysfunction. Endogenous cholesterol and phospholipids in brain undergo auto-oxidation by enzymatic as well as non-enzymatic modes leading to the formation of by-products such as 4-hydroxynonenal and oxysterols. Among various oxysterols, 7-ketocholesterol (7KCh) is one of the major toxic components involved in altering neuronal lipid metabolism, contributing to inflammation and nerve cell damage. More evidently 7KCh is proven to induce oxidative stress and affects membrane permeability. Loss in mitochondrial membrane potential affects metabolism of cell organelles such as lysosomes and peroxisomes which are involved in lipid and protein homeostasis. This in turn could affect amyloidogenesis, tau protein phosphorylation and accumulation in pathological conditions of neurodegenerative diseases. Lipid alterations and the consequent pathogenic protein accumulation, results in the damage of cell organelles and microglial cells. This could be a reason behind disease progression and predominantly reported characteristics of neurodegenerative disorders such as Alzheimer’s disease. This review focuses on the role of 7KCh mediated neurodegenerative Alzheimer’s disease with emphasis on alterations in the lipid raft microdomain. In addition, current trends in the significant therapies related to 7KCh inhibition are highlighted.

Abbreviations

MPTP
1-Methyl-1, 2, 3, 6-tetrahydropyridine
7KCh
7-ketocholesterol
24S-OHC
24S-hydroxycholesterol
27-OHC
27-hydroxycholesterol
ACOX1
acyl-coA oxidase -1
ATF6
activating transcription factor 6
ATP
adenosine triphosphate
αSyn
alpha synuclein
AD
Alzheimer’s disease
amyloid beta
APP
amyloid precursor protein
ApoE
apolipoprotein E
ASK 1
apoptosis signal-regulating kinase 1
ABCA 1
ATP-binding cassette transporter A1
ABCG 1
ATP-binding cassette transporter G1
Abcd1
ATP binding cassette subfamily D 1
Abcd2
ATP binding cassette subfamily D 2
Bcl-2
B cell lymphoma -2
BAX
B cell lymphoma associated X
BACE 1
beta-site amyloid precursor protein cleaving enzyme
Bid
BH3 interacting- domain death agonist
BBB
blood brain barrier
BDNF
brain-derived neurotrophic factor
Ca2+
calcium
CMA
chaperone-mediated autophagy
CYP7A1
cholesterol 7 alpha-hydroxylase
CHOP
C/EBP homologous protein
Chr
chromosome
CoQ10
coenzyme Q10
CYPs
cytochrome p450
DRM
detergent resistant membrane
Drp1
dynamin-related protein 1
ER
endoplasmic reticulum
ERK
extracellular signal-regulated kinases
EALP
endosome-autophagosome-lysosome pathway
ESCRT
endosomal sorting complex required for transport
GSH
glutathione
eIF2α
eukaryotic translation initiator factor-2α
GRP78
glucose-related protein 78
GSK 3
glycogen synthase kinase -3
HO-1
heme oxygenase-1
HT-29
human colon cancer cell line
HUVEC-CS
human umbilical vein endothelial cells
H2O2
hydrogen peroxide
ICAM
intercellular adhesion molecule
IRE1
inositol-requiring enzyme-1
ILVs
intraluminal vesicles
JNK
c-Jun N-terminal kinase
iNOS
Inducible nitric oxide synthase
LDL
Low-density lipoprotein
LDLR
low-density lipoprotein receptor
LAMP2
lysosomal membrane-associated protein 2
LMP
lysosomal membrane permeabilization
MC-SF
macrophage colony-stimulating factor
MMP-9
matrix metalloproteinases
MAMs
mitochondria-associated membranes
mt DNA
mitochondrial DNA
Fis1
mitochondrial fission protein 1
Mfn1
mitofisin-1
Mfn2
mitofisin -2
MVBs
multivesicular bodies
Mfp2
multifunctional protein- 2
NOX-4
NADPH oxidase 4
NGF
Nerve growth factor
NFT
neurofibrillary tangle
NADH
nicotinamide adenine dinucleotide
NADPH
nicotinamide adenine dinucleotide phosphate
NFE2L2
nuclear factor, erythroid 2- like 2
NF-κB
nuclear factor kappa B
Opa1
optic atrophy protein
PERK
pancreatic ER kinase
PI3K
phosphatidylinositol 3-kinase
p53
phosphoprotein 53
PARP-1
poly (ADP-ribose) polymerase
PGE2
prostaglandin E2
PSEN1
presenilin 1
PSEN2
presenilin 2
P38
p38 mitogen-activated protein kinase
ROS
reactive oxygen species
Sig-1R
sigma-1 receptor
Src
steroid activated protein
TFEB
transcription factor EB
TNF-R2
TNF- receptor 2
UPR
unfolded protein response
VLCFAs
very long chain fatty acids
VWF
von Willebrand factor
XBP1
X-box binding protein 1
X-ALD
X-linked adrenoleukodystrophy

Keywords

Neurodegenerative diseases
Alzheimer’s disease
7-Ketocholesterol
Neurons
Oxidative stress
Amyloid-β peptide
Mitochondria
Lysosome
Peroxisome
Endoplasmic reticulum
Microglial activation

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