J Vet Sci.  2018 May;19(3):319-330. 10.4142/jvs.2018.19.3.319.

Microglial involvement in the development of olfactory dysfunction

• Seo Y
• Kim HS
• Kang KS

• KMID: 2412122
• DOI: http://doi.org/10.4142/jvs.2018.19.3.319

Abstract

Olfactory impairment is the most common clinical manifestation among the elderly, and its prevalence increases sharply with age. Notably, growing evidence has shown that olfactory dysfunction is the first sign of neurodegeneration, indicating the importance of olfactory assessment as an early marker in the diagnosis of neurological disorders. In this review, we describe the nature of olfactory dysfunction and the advantage of using animal models in olfaction study, and we include a brief introduction to olfactory behavior tests widely used in this field. The contribution of microglia in the neurodegenerative processes including olfactory impairment is then discussed to provide a comprehensive description of the physiopathological role of interactions between neurons and microglia within the olfactory system.

Keyword

Niemann-Pick disease type C; microglia; neurodegenerative diseases; smell

MeSH Terms

Aged
Behavior Rating Scale
Diagnosis
Humans
Microglia
Models, Animal
Nervous System Diseases
Neurodegenerative Diseases
Neurons
Prevalence
Smell

Figure

• 

  Fig. 1 Cholesterol accumulation in the olfactory system of Niemann-Pick disease type C (NPC) mice. Representative filipin-stained images showing intracellular cholesterol in the olfactory epithelium (OE; A) and the olfactory bulb (OB; B) of 8-week-old wild-type (WT) and NPC model mice. Scale bars = 100µm (A and B).

• 

  Fig. 2 Distribution patterns of olfactory sensory neurons and other periglomerular neurons in the olfactory epithelium (OE; A) and olfactory bulb (OB; B) revealed by immunohistochemical analysis. Relative expression intensity of olfactory marker protein (OMP) in Niemann-Pick disease type C (NPC) mice is down-regulated compared to that in wild-type (WT) controls in both the OE (A) and OB (B), indicating that the number of olfactory sensory neurons are decreased in NPC status. (C) Tyrosine hydroxylase (TH)-expressing neurons, a type of periglomerular neuron, are damaged in the OB of NPC mice compared to those of WT counterparts. Scale bars = 50 µm (A and C), 100 µm (B).

• 

  Fig. 3 A simplified schematic diagram of neuron-microglia involvement in olfactory dysfunction in Niemann-Pick disease type C (NPC) mice. Briefly, NPC mutation upregulates intracellular cholesterol followed by p38 MAPK signaling activation in microglia. In response to this activation, multiple cytotoxic molecules are secreted, leading to direct neurotoxicity. In addition, p38 MAPK signaling enhances the maturation of microglial cathepsin S, thereby increasing the shedding of neuronal chemokine Cx3cl1. The Cx3cl1 secretion results in the recruitment of Cx3cr1 (a specific receptor for Cx3cl1)-bearing microglia, which eventually results in repetitive cycling between neurons and microglia in the NPC-affected OB. Importantly, blockage of this pathway either by a Cx3cl1 neutralizing antibody or by the cathepsin S inhibitor LHVS successfully prevents microglial activation and, in turn, restores olfaction of NPC mice. This illustration is a modified version of the ‘The Table of Contents Image’ in our recently published article as stated. Source: Seo Y, et al. Glia 2016, 64(12), 2291-2305.

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