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

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  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

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.

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Abbreviations

Aβ:

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

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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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Authors and Affiliations

  1. Laboratory of Molecular NeuroTherapeutics, Boston University School of Medicine, 72 East Concord Street, L-606, Boston, MA, 02118, USA

    Megan M. Varnum & Tsuneya Ikezu

  2. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA

    Megan M. Varnum & Tsuneya Ikezu

  3. Department of Neurology, Boston University School of Medicine, Boston, MA, USA

    Tsuneya Ikezu

  4. Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, MA, USA

    Megan M. Varnum

  5. Alzheimer’s Disease Center, Boston University School of Medicine, Boston, MA, USA

    Tsuneya Ikezu

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  1. Megan M. Varnum
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Correspondence to Tsuneya Ikezu.

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Varnum, M.M., Ikezu, T. The Classification of Microglial Activation Phenotypes on Neurodegeneration and Regeneration in Alzheimer’s Disease Brain. Arch. Immunol. Ther. Exp. 60, 251–266 (2012). https://doi.org/10.1007/s00005-012-0181-2

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  • DOI: https://doi.org/10.1007/s00005-012-0181-2

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