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Heat Shock Proteins, a Key Modulator of Neuroinflammation in Alzheimer’s Disease

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Heat Shock Proteins in Inflammatory Diseases

Part of the book series: Heat Shock Proteins ((HESP,volume 22))

Abstract

Introduction

Heat shock proteins (Hsp) are a key player to maintain protein homeostasis and folding in neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), etc. Hsp are associated with NDs via induction of proper folding of toxic misfolded protein. AD is the second most common neurodegenerative disease worldwide and is characterized by accumulation of Aβ42 plaques and hyperphosphorylated tau that results in cognitive decline, neuronal death and affects brain structure. From the last past decade, several researchers proved that AD is not restricted to the brain, but it also manipulates the immune response and activation of inflammatory cells. AD is the amalgam of neurobiology and Immunology. One of the core pathologies of AD is neuroinflammation which activates the innate immune response followed by activation of microglia (macrophages), a resident immune cell of CNS and astroglia cells. Amyloid plaques and neurofibrillary tangles activate neuroinflammatory components such as microglia which further induce the production of a variety of proinflammatory cytokines, ROS, nitric oxide, eicosanoids, etc. Previous studies have shown that apart from Hsp molecular chaperone function, it also plays a role in neuroinflammation and disease-related signaling mechanisms. In here, we aim to summarize the details of Hsp as a key modulator of neuroinflammation in Alzheimer’s Disease.

Methods

The authors reviewed most of the relevant papers of Hsp and their role in neuroinflammation in AD.

Results

Available data suggest that Hsp plays a protective role in neuroinflammation by acting as an immunomodulator in the central nervous system and is also associated with astrocytes in Aβ42 plaques in the brain of AD patients. It has been demonstrated that several signaling pathways are activated by cytokines such as TNF-α, INF-γ, IL-1β, etc. in the brain which exacerbates the AD-related pathologies and overexpression of Hsp decreases the inflammatory cytokines in the brain and decrease the progression and severity of the disease.

Conclusions

Hsp are significantly involved in the modulation of neuroinflammation via interacting with inflammation-causing molecules and helps in the prevention of neuroinflammation in AD. It is used as a potential therapeutic target for the prevention of AD-related pathologies. The supplementation of compounds, known as inducers/co-inducers of Hsp in AD might be one of the potential therapeutic targets to treat/prolong the AD related pathologies in future. Moreover, membrane lipid rearrangement and nanoparticle-based therapies are also involved in decreasing the neuroinflammation via increasing the Hsp level at the site of neuroinflammation. Thus, apart from the supplementation of drugs to modulate the Hsp level, the interaction of Hsp with inflammatory cells and their affinity to reduce/inactivate them should be a more focused area in the case of AD and need to be extensively studied to get better therapeutic approach to treat the AD.

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Abbreviations

17-AAG:

17-allylamino-demethoxygeldanamycin

AA:

arachidonic acid

AAVs:

adeno-associated viruses

ACD:

α-crystallin domain

AD:

Alzheimer’s disease

AP1:

activator protein 1

ApoE:

apolipoprotein E

APP:

amyloid precursor protein

Appl:

amyloid precursor protein like

ASK1:

apoptosis signal-regulating kinase 1

ATP:

adenosine triphosphate

Aβ:

amyloid-β

BACE-1:

beta-site amyloid precursor protein cleaving enzyme – 1

BAX:

Bcl-2-associated X protein

BBB:

blood brain barrier

Bcl2:

B-cell lymphoma 2

CD:

cluster of differentiation

Clp:

Casein lytic proteinase

CNS:

central nervous system

COX-2:

cyclooxygenase-2

CPX:

cyclooxygenase – 2

CSF:

cerebrospinal fluid

CTF:

C-terminal fragment

CTL:

cytotoxic T lymphocytes

CTR:

c-terminal region

CvHsp:

cardiovascular heat shock protein

DAXX:

death domain associated protein

DHMN2C:

distal hereditary motor neuropathy 2C

DMPK:

myotonic dystrophy protein kinase

DNA:

deoxyribonucleic acid

DPPC:

dipalmitoyl phosphatidyl choline

EEVD:

Glu-Glu-Val-Asp (Glu- glutamic acid, Val- Valine, Asp- Aspartic acid)

eIF4E:

eukaryotic translation initiation factor

EPF:

extracellular protein factor

ER:

endoplasmic reticulum

ERGIC:

ER-Golgi intermediate compartment

ERK:

extracellular-signal regulated kinases

FLT3:

FMS-like tyrosine kinase-3

GGA:

Geranylgeranyl acetone

GRP78:

glucose-regulated protein 78kD

HD:

Huntington’s disease

HSE:

heat shock elements

HSF:

heat shock factor

Hsp:

heat shock proteins

HTPG:

high-temperature protein G

IL:

interleukins

INF:

interferone

iNOS:

inducible nitric oxide synthase

JAK2:

Janus kinase

JNK:

c-Jun N-terminal kinase

kDa:

kilo Dalton

LPS:

lipopolysaccharides

MAPK:

mitogen-activated protein kinase

MCP-1:

macrophage chemo-attractant protein-1

M-CSF:

macrophage colony-stimulating factor

MHC:

major histocompatibility complex

MIP-1α:

macrophage inflammatory peptide

MKBP:

myotonic dystrophy kinase binding protein

MN:

motor neuron

MS:

multiple sclerosis

MtUPR:

mitochondrial related unfolding protein response

Myd88:

myeloid differentiation factor 88

NDDs:

neurodegenerative diseases

NF-kB:

nuclear factor-kappa B

NFT:

neurofibrillary tangles

NO:

nitric oxide

NOD:

leucine rich repeat and pyrin containing protein 3 (NLRP3)

NTR:

N-terminal region

ODF1:

outer dense fiber protein 1

PD:

Parkinson’s disease

PG:

prostaglandins

PI3K:

phosphatidylinositol-3-kinase

PP1:

protein phosphatase 1

PS:

presenilin

RAF:

rapidly accelerated fibrosarcoma

RIP:

receptor-interacting kinase

ROS:

reactive oxygen species

SAPK:

stress-activated kinases

sAPP:

soluble amyloid precursor protein

sHsp:

small heat shock protein

STAT-1:

signal transducers and activator of transcription-1

TBI:

traumatic brain injury

TCTEL1:

T-complex-associated-testis-expressed 1-like 1

TGF:

transforming growth factor

TLR:

toll like receptor

TNF:

tumor necrosis factor

TRAP:

tryptophan regulated attenuation protein

WD/EPF domain:

WD (Tryptophan-aspartic acid (W-D) dipeptide), epf-domain

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Acknowledgements

The authors are very much thankful to Science and Engineering Research Board (SERB), New Delhi, India (No. EMR/2016/006911/HS), Gujarat Council on Science & Technology (GUJCOST/MRP/2015-16/2680) Gujarat for financial support to AKT and DST-Innovation of Science Pursuit for Inspire Research (INSPIRE), New Delhi for financial support to KP (IF140990).

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All authors declare they have no conflict of interest.

Ethical Approval for Studies Involving Humans

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  1. Genetics & Developmental Biology Laboratory, Department of Biological Sciences & Biotechnology, Institute of Advanced Research/IIAR, Koba Institutional Area, Gandhinagar, Gujarat, India

    Komal Panchal, Vidhi Bhatt, Mahima Raval & Anand Krishna Tiwari

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Correspondence to Anand Krishna Tiwari .

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  1. Department of Medicine and Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer Center University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Alexzander A. A. Asea

  2. Department of Medicine and Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer Center University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA

    Punit Kaur

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Panchal, K., Bhatt, V., Raval, M., Tiwari, A.K. (2020). Heat Shock Proteins, a Key Modulator of Neuroinflammation in Alzheimer’s Disease. In: Asea, A.A.A., Kaur, P. (eds) Heat Shock Proteins in Inflammatory Diseases. Heat Shock Proteins, vol 22. Springer, Cham. https://doi.org/10.1007/7515_2020_12

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