Role of Microglia in Regulating Cholesterol and Tau Pathology in Alzheimer’s Disease

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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Acknowledgements

We are grateful to Chinnathambi lab members for their scientific discussions, helpful suggestions, and we highly appreciate the critical reading of the manuscript.

Funding

This project is supported in part by grant from in-house CSIR-National Chemical Laboratory grant MLP029526.

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SN and SC prepared the initial draft of the paper. HC and MC helped in preparing figure modifications and critical reading for the manuscript. SC conceived the idea of the work, supervised, resource provided, and wrote the paper. All authors read and approved the final paper.

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Correspondence to Subashchandrabose Chinnathambi.

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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 (2020). https://doi.org/10.1007/s10571-020-00883-6

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Keywords

  • Alzheimer’s disease
  • Amyloid-β protein
  • Tau hyperphosphorylation
  • Cholesterol
  • Microglia