The Classification of Microglial Activation Phenotypes on Neurodegeneration and Regeneration in Alzheimer’s Disease Brain

Review

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline of cognitive function. There is no therapy that can halt or reverse its progression. Contemporary research suggests that age-dependent neuroinflammatory changes may play a significant role in the decreased neurogenesis and cognitive impairments in AD. The innate immune response is characterized by pro-inflammatory (M1) activation of macrophages and subsequent production of specific cytokines, chemokines, and reactive intermediates, followed by resolution and alternative activation for anti-inflammatory signaling (M2a) and wound healing (M2c). We propose that microglial activation phenotypes are analogous to those of macrophages and that their activation plays a significant role in regulating neurogenesis in the brain. Microglia undergo a switch from an M2- to an M1-skewed activation phenotype during aging. This review will assess the neuroimmunological studies that led to characterization of the different microglial activation states in AD mouse models. It will also discuss the roles of microglial activation on neurogenesis in AD and propose anti-inflammatory molecules as exciting therapeutic targets for research. Molecules such as interleukin-4 and CD200 have proven to be important anti-inflammatory mediators in the regulation of neuroinflammation in the brain, which will be discussed in detail for their therapeutic potential.

Keywords

Alzheimer’s disease Microglia Neurogenesis Neuroinflammation 

Abbreviations

Amyloid β-peptide

AD

Alzheimer’s disease

AICD

APP intracellular domain

APP

Amyloid precursor protein

ARG1

Arginase 1

ATP

Adenosine triphosphate

CD200

Cluster of differentiation 200 (aka OX2)

CNS

Central nervous system

Dok

Downstream of tyrosine kinase

Erk

Extracellular signal-regulated kinase

EAE

Experimental autoimmune encephalomyelitis

EAU

Experimental autoimmune uveoretinitis

FGF-2

Fibroblast growth factor-2

HPA

Hypothalamo-pituitary-adrenal

IGF-1

Insulin-like growth factor-1

IgSF

Immunoglobulin superfamily

IFN-γ

Interferon-γ

IL

Interleukin

ITIM

Immunotyrosine-based inhibitory motif

JNK

c-Jun N-terminal kinase

LPS

Lipopolysaccharide

LTP

Long-term potentiation

MAPK

Mitogen-activated protein kinase

MDP

Muramyl dipeptide

MS

Multiple sclerosis

NFT

Neurofibrillary tangle

NLR

NOD-like receptor

NOD

Nucleotide oligomerization domain

NOS

Nitric oxide synthase

NPC

Neural progenitor cell

NSAID

Non-steroidal anti-inflammatory drug

NSC

Neural stem cell

PAMP

Pathogen-associated molecular pattern

PRR

Pathogen recognition receptor

PS

Presenilin

RasGAP

RAS p21 protein activator 1

SGZ

Subgranular zone

SH2

Src homology 2

SVZ

Subventricular zone

TGF-β

Transforming growth factor-β

TLR

Toll-like receptor

TNF-α

Tumor necrosis factor-α

YM1

Chitinase 3-like 3

Notes

Acknowledgments

We would like to thank Seiko Ikezu and Maya Woodbury for editing the manuscript. This work was supported in part by National Institute of Health grants 5T32GM008541 to M.M. Varnum, and MH072539 and AG032600 to T. Ikezu.

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Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2012

Authors and Affiliations

  1. 1.Laboratory of Molecular NeuroTherapeuticsBoston University School of MedicineBostonUSA
  2. 2.Department of Pharmacology and Experimental TherapeuticsBoston University School of MedicineBostonUSA
  3. 3.Department of NeurologyBoston University School of MedicineBostonUSA
  4. 4.Program in Biomolecular PharmacologyBoston University School of MedicineBostonUSA
  5. 5.Alzheimer’s Disease CenterBoston University School of MedicineBostonUSA

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