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



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.


Alzheimer’s disease Microglia Neurogenesis Neuroinflammation 


Amyloid β-peptide


Alzheimer’s disease


APP intracellular domain


Amyloid precursor protein


Arginase 1


Adenosine triphosphate


Cluster of differentiation 200 (aka OX2)


Central nervous system


Downstream of tyrosine kinase


Extracellular signal-regulated kinase


Experimental autoimmune encephalomyelitis


Experimental autoimmune uveoretinitis


Fibroblast growth factor-2




Insulin-like growth factor-1


Immunoglobulin superfamily






Immunotyrosine-based inhibitory motif


c-Jun N-terminal kinase




Long-term potentiation


Mitogen-activated protein kinase


Muramyl dipeptide


Multiple sclerosis


Neurofibrillary tangle


NOD-like receptor


Nucleotide oligomerization domain


Nitric oxide synthase


Neural progenitor cell


Non-steroidal anti-inflammatory drug


Neural stem cell


Pathogen-associated molecular pattern


Pathogen recognition receptor




RAS p21 protein activator 1


Subgranular zone


Src homology 2


Subventricular zone


Transforming growth factor-β


Toll-like receptor


Tumor necrosis factor-α


Chitinase 3-like 3



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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