Abstract
Cholesterol, a principal constituent of the cell membrane, plays a crucial role in the brain by regulating the synaptic transmission, neuronal signaling, as well as neurodegenerative diseases. Defects in the cholesterol trafficking are associated with enhanced generation of hyperphosphorylated Tau and Amyloid-β protein. Tau, a major microtubule-associated protein in the brain, is the key regulator of the mature neuron. Abnormally hyperphosphorylated Tau hampers the major functions related to microtubule assembly by promoting neurofibrillary tangles of paired helical filaments, twisted ribbons, and straight filaments. The observed pathological changes due to impaired cholesterol and Tau protein accumulation cause Alzheimer's disease. Thus, in order to regulate the pathogenesis of Alzheimer's disease, regulation of cholesterol metabolism, as well as Tau phosphorylation, is essential. The current review provides an overview of (1) cholesterol synthesis in the brain, neurons, astrocytes, and microglia; (2) the mechanism involved in modulating cholesterol concentration between the astrocytes and brain; (3) major mechanisms involved in the hyperphosphorylation of Tau and amyloid-β protein; and (4) microglial involvement in its regulation. Thus, the answering key questions will provide an in-depth information on microglia involvement in managing the pathogenesis of cholesterol-modulated hyperphosphorylated Tau protein.
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Abbreviations
- AD:
-
Alzheimer’s disease
- Aβ:
-
Amyloid-β
- FAD:
-
Familial Alzheimer’s disease
- APP:
-
Amyloid precursor protein
- PS-1 & 2:
-
Presenilin-1 & 2
- CNS:
-
Central nervous system
- BBB:
-
Blood–brain barrier
- HMG-CoA:
-
3-Hydroxy-3-methylglutaryl-CoA
- ABCA1:
-
ATP-binding cassette transporter
- CERP:
-
Cholesterol efflux regulatory protein
- NPC:
-
Niemann–Pick type C
- ACAT1/SOAT1:
-
Acyl-coenzyme A: cholesterol acyltransferase-1
- 24- OHC:
-
24-Hydroxycholesterol
- LXR:
-
Liver X receptor
- CaMKII:
-
Calcium and calmodulin-dependent protein kinase- II
- TLR4:
-
Toll-like receptor-4
- CX3CR1:
-
CX3C chemokine receptor-1
- PI3K:
-
Phosphoinositide 3-kinase
- ITAM:
-
Immunoreceptor tyrosine-based activation motif
- SORL1:
-
Sortilin-related receptor 1
- ER:
-
Endoplasmic reticulum
- APOE:
-
Apolipoprotein E
- SREBPs:
-
Sterol regulatory element-binding proteins
- LDL:
-
Low-density lipoprotein
- VLDLR:
-
Very low-density lipoprotein receptor
- LRP1:
-
LDL receptor-related protein 1
- GWAS:
-
Genome-wide association studies
- TREM2:
-
Triggering receptor expressed on myeloid cells 2
- RCT:
-
Reverse cholesterol transport
- MAP:
-
Microtubule-associated protein
- PHFs:
-
Paired helical filaments
- GSK-3:
-
Glycogen synthase kinase-3
- cdk5:
-
Cyclin-dependent protein kinase-5
- PKA:
-
Protein kinase A
- SIGLEC:
-
Sialic acid-binding immunoglobulin-type lectins
- BIN1:
-
Bridging integrator 1
- CME:
-
Clathrin-mediated endocytosis
- LOAD:
-
Late-onset AD
- HSPG:
-
Heparin sulfate proteoglycan
- FAK:
-
Focal adhesion kinase
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We are grateful to Chinnathambi lab members for their scientific discussions, helpful suggestions, and we highly appreciate the critical reading of the manuscript.
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Nanjundaiah, S., Chidambaram, H., Chandrashekar, M. et al. Role of Microglia in Regulating Cholesterol and Tau Pathology in Alzheimer’s Disease. Cell Mol Neurobiol 41, 651–668 (2021). https://doi.org/10.1007/s10571-020-00883-6
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DOI: https://doi.org/10.1007/s10571-020-00883-6