Upregulation of cannabinoid receptor type 2, but not TSPO, in senescence-accelerated neuroinflammation in mice: a positron emission tomography study

Satoru Yamagishi,Dai Fukumoto,Masato Nakamura,Hideo Tsukada,Chika Takizawa,Yurika Iga,Hiroyuki Ohba,Yasuomi Ouchi,Kohji Sato,Takeharu Kakiuchi,Shingo Nishiyama

doi:10.1186/s12974-019-1604-3

Abstract

BackgroundMicroglial cells are activated in response to changes in brain homeostasis during aging, dementia, and stroke. Type 2 endocannabinoid receptors (CB2) and translocator protein 18 kD (TSPO) are considered to reflect distinct aspects of microglia-related neuroinflammatory responses in the brain. CB2 activation is considered to relate to the neuroprotective responses that may occur predominantly in the early stage of brain disorders such as Alzheimer’s disease, while an increase in TSPO expression tends to occur later during neuroinflammation, in a proinflammatory fashion. However, this information was deduced from studies with different animal samples under different experimental settings. In this study, we aimed to examine the early microglial status in the inflammation occurring in the brains of senescence-accelerated mouse prone 10 (SAMP10) mice, using positron emission tomography (PET) with CB2 and TSPO tracers, together with immunohistochemistry.MethodsFive- and 15-week-old SAMP10 mice that undergo neurodegeneration after 7 months of age were used. The binding levels of the TSPO tracer (R)-[11C]PK11195 and CB2 tracer [11C]NE40 were measured using PET in combination with immunohistochemistry for CB2 and TSPO. To our knowledge, this is the first study to report PET data for CB2 and TSPO at the early stage of cognitive impairment in an animal model.ResultsThe standard uptake value ratios (SUVRs) of [11C]NE40 binding were significantly higher than those of (R)-[11C]PK11195 binding in the cerebral cortical region at 15 weeks of age. At 5 weeks of age, the [11C]NE40 SUVR tended to be higher than the (R)-[11C]PK11195 SUVR. The (R)-[11C]PK11195 SUVR did not significantly differ between 5- and 15-week-old mice. Consistently, immunostaining analysis confirmed the upregulation of CB2, but not TSPO.ConclusionsThe use of the CB2 tracer [11C]NE40 and/or an immunohistochemical approach allows evaluation of the role of microglia in acute neuroinflammatory processes in the early stage of neurodegeneration. The present results provide in vivo evidence of different responses of two types of microglia to senescence-accelerated neuroinflammation, implying the perturbation of microglial balance by aging. Specific treatment for CB2-positive microglia might help ameliorate senescence-related neuroinflammation and the following neurodegeneration.

Highlights

Microglial cells are activated in response to changes in brain homeostasis during aging, dementia, and stroke
Significant correlations were found between [11C]NE40 Standard uptake value ratio (SUVR) and (R)-[11C]PK11195 SUVRs measured in the brains of 5-week-old mice (r = 0.501, p = 0.006; Fig. 2c), whereas no significant correlations were found in either 15-week-old senescenceaccelerated mouse prone 10 (SAMP10) mice (Fig. 2d) or 15-week-old SAMPR1 mice (r = 0.409, p = 0.117; Additional file 2: Figure S2B)
In Additional file 2: Figure S2, data from 15week-old SAMR1 mice are shown to help understand the changes seen in SAMP10 mice

Summary

Introduction

Microglial cells are activated in response to changes in brain homeostasis during aging, dementia, and stroke. CB2 activation is considered to relate to the neuroprotective responses that may occur predominantly in the early stage of brain disorders such as Alzheimer’s disease, while an increase in TSPO expression tends to occur later during neuroinflammation, in a proinflammatory fashion This information was deduced from studies with different animal samples under different experimental settings. We aimed to examine the early microglial status in the inflammation occurring in the brains of senescenceaccelerated mouse prone 10 (SAMP10) mice, using positron emission tomography (PET) with CB2 and TSPO tracers, together with immunohistochemistry Microglia change both morphologically and functionally from their resting state to their activated state in several neuroinflammatory and neurodegenerative diseases. It is currently well reported that the accumulation of (R)-[11C]PK11195 or the second-generation tracer [18F]DPA714 occurs relatively late after brain injury resulting from toxin injection [6] or traumatic insult [7, 8]

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