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Microglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease

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Abstract

The prominent pathological consequences of Alzheimer’s disease (AD) are the misfolding and mis-sorting of two cellular proteins, amyloid-β and microtubule-associated protein Tau. The accumulation of toxic phosphorylated Tau inside the neurons induces the increased processing of amyloid-β-associated signaling cascade and vice versa. Neuroinflammation-driven synaptic depletion and cognitive decline are substantiated by the cross talk of activated microglia and astroglia, leading to neuron degeneration. Microglia are the brain-resident immune effectors that prove their diverse functions in maintaining CNS homeostasis via collaboration with astrocytes and T lymphocytes. Age-related senescence and chronic inflammation activate microglia with increased pro-inflammatory markers, oxidative damage and phagocytosis. But the improper processing of misfolded protein via lysosomal pathway destines the spreading of ‘seed’ constituents to the nearby healthy neurons. Primed microglia process and present self-antigen such as amyloid-β and modified Tau to the infiltrated T lymphocytes through MHC I/II molecules. After an effective conversation with CD4+ T cells, microglial phenotype can be altered from pro-active M1 to neuro-protective M2 type, which corresponds to the tissue remodeling and homeostasis. In this review, we are focusing on the change in functionality of microglia from innate to adaptive immune response in the context of neuroprotection, which may help in the search of novel immune therapy in AD.

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Abbreviations

BACE1:

Beta secretase 1

PTMs:

Post-translational modifications

BBB:

Blood–brain barrier

CNS:

Central nervous system

ROS:

Reactive oxygen species

NO:

Nitric oxide

iNOS:

Inorganic nitric oxide synthase

CD:

Cluster of differentiation

MHC:

Major histocompatibility complex

TGFβ:

Transforming growth factor β

TNFα:

Tumor necrosis factor α

IL:

Interleukin

IFN:

Interferon

TH :

Helper T cell

Treg :

Regulatory T cell

KO:

Knockout

CR:

Complement receptor

NFκB:

Nuclear factor κ for B cell

mTOR:

Mammalian target for rapamycin

Akt:

Protein kinase B

ATP:

Adenosine tri-phosphate

APC:

Antigen-presenting cell

TREM2:

Triggering receptor expressed on myeloid cells 2

ApoE:

Apolipoprotein E

NFκB:

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

p38-MAPK:

p38-mitogen-activated protein kinases

CSF1R:

Colony-stimulating factor-1 receptor

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Acknowledgements

This project is supported in part by grants from the Department of Biotechnology, Neuroscience Task Force (Medical Biotechnology-Human Development & Disease Biology DBT-HDDB)-BT/PR/15780/MED/122/4/2016 and in-house CSIR-National Chemical Laboratory Grant MLP029526. Special thanks to Ms. Nalini Gorantla, Mr. Abhishek Balmik and Ms. Shweta Sonawane for proofreading the manuscript. Rashmi Das acknowledges the fellowship from University Grant Commission (UGC) India.

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  1. Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India

    Rashmi Das & Subashchandrabose Chinnathambi

  2. Academy of Scientific and Innovative Research (AcSIR), Pune, 411008, India

    Rashmi Das & Subashchandrabose Chinnathambi

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Das, R., Chinnathambi, S. Microglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease. Cell. Mol. Life Sci. 76, 3681–3694 (2019). https://doi.org/10.1007/s00018-019-03132-2

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