The role of microglia in prion diseases and possible therapeutic targets: a literature review

ABSTRACT

Creutzfeldt-Jakob disease (CJD) is a rare and fatal condition that leads to progressive neurodegeneration due to gliosis, vacuolation of central nervous system tissue, and loss of neurons. Microglia play a crucial role in maintaining Central Nervous System (CNS) homoeostasis, both in health and disease, through phagocytosis and cytokine production. In the context of CJD, the immunomodulatory function of microglia turns it into a cell of particular interest. Microglia would be activated by infectious prion proteins, initially acquiring a phagocytic and anti-inflammatory profile (M2), and producing cytokines such as IL-4, IL-10, and TGF-β. Therefore, microglia are seen as a key target for the development of new treatment approaches, with many emerging strategies to guide it towards a beneficial role upon neuroinflammation, by manipulating its metabolic pathways. In such a setting, many cellular targets in microglia that can be involved in phenotype modulation, such as membrane receptors, have been identified and pointed out as possible targets for further experiments and therapeutic approaches. In this article, we review the major findings about the role of microglia in CJD, including its relationship to some risk factors associated with the development of the disease. Furthermore, considering its central role in neural immunity, we explore microglial connection with other elements of the immune system and cell signalling, such as inflammasomes, the complement and purinergic systems, and the latest finding strategies to guide these cells from harmful to beneficial roles.

KEYWORDS:

• Creutzfeldt-Jakob disease
• microglia
• neuroinflammation pathways

LIST OF ABREVIATIONS

CJD – Creutzfeldt-Jakob disease

CNS – Central Nervous System

sCJD – Sporadic Creutzfeldt-Jakob disease

PrP^C – Cellular prion protein

PrP^Sc - Infectious prion proteins

M2 – Anti-inflammatory profile

M1 – Proinflammatory archetype

TSE - Transmissible spongiform encephalopathy

GSS - Gerstmann-Straussler-Scheinker disease

FFI - Fatal familial insomnia

hCJD - Hereditary Creutzfeldt-Jakob disease

aCJD – Acquired Creutzfeldt-Jakob disease

BSE – Bovine spongiform encephalopathy

vCJD – Variant Creutzfeldt-Jakob disease

HvCJD – Heidenhain Creutzfeldt-Jakob disease variant

SAP – Serum amyloid P componentPRRs - Pattern recognition receptors

CSF - Cerebrospinal fluid

DAM - Disease-associated microglia

MGnD - Microglia neurodegenerative phenotype

ROS - Reactive oxygen species

TLR - Toll-like receptors

NOX - NADPH oxidases

MFGE8 - Milk fat globule epidermal growth factor 8

AP-1 - Activator

- Amyotrophic lateral sclerosis

A1 - Reactive astrocytes

TREM2 - Triggering receptor expressed in myeloid cells 2

RML6 - Rocky Mountain Laboratories scrapie strain

PRNP - Prion protein gene

M – Methionine

V – Valine

LPS – Lipopolysaccharide

TNFα - Tumour necrosis factor-α

C/EBPα - CCAAT/enhancer-binding protein alpha

STAT - Signal transducer and activator of transcription

NFkB - Nuclear factor kappa-light-chain-enhancer of activated B cells

JAK - Cytokine-activated Janus kinase

GPCRs - G protein-coupled receptors

TGF-β - Transforming growth factor β

CCL2 - C-C Motif Chemokine Ligand 2

PGE2 - Prostaglandin E2

NOX2 - NADPH oxidase 2

CB2 - Endocannabinoid type 2 receptor

p38-MAPK - p38 mitogen-activated protein kinase

miRNAs – MicroRNAs

TRAF-6 - TNF receptor associated factor-6

DAMP - Damage-associated molecular pattern

P2X7R - P2X7 receptor

DCA – Dichloroacetate

MS - Multiple sclerosis

DMF – Dimethylfumarate

AR - Aldose reductase

Acknowledgments

This study was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; #2017/16443-0).

Authors’ contributions

ASLFM, JLDL, MCSM, NFM, ARM, IAL, FSC, and JCCS wrote original draft, and gathered the data, DBG wrote final draft, BGD wrote final draft and made the schematic illustration, JCCS overviewed the review as the senior author. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.