Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer's disease mouse model

Schmöle, Anne-Caroline; Lundt, Ramona; Ternes, Svenja; Albayram, Önder; Ulas, Thomas; Schultze, Joachim L.; Bano, Daniele; Nicotera, Pierluigi; Alferink, Judith; Zimmer, Andreas

doi:10.1016/j.neurobiolaging.2014.09.019

Cited by 76 publications

(83 citation statements)

References 22 publications

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“…These data are consistent with our previous studies [51] and data obtained by others [65,88], and might contribute to the novel hypothesis of the involvement of CB2 receptors in the attenuation of nociceptive response at the spinal level in animal models of neuropathic pain [67]. Moreover, CB2 was described as being involved in not only the peripheral inflammatory response [60] but also central nervous system inflammation [17,69]. Our recent studies have shown the participation of CB2 receptors in glial inflammatory response [53], which is known to contribute to the development and maintenance of neuropathic pain [65,83,89].…”

Section: Discussionsupporting

confidence: 91%

The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain

Małek

Kostrzewa

Makuch

et al. 2016

Pharmacological Research

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Section: Discussionsupporting

confidence: 91%

The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain

Małek

Kostrzewa

Makuch

et al. 2016

Pharmacological Research

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“…The contribution of IL-23 to AD pathogenesis is not fully understood [81]. Previous studies demonstrated that the cytokine network in APP/PS1 mice is indiscriminate as compared to that in WT mice [82–86]. In the present study, we measured 17 cytokines in the plasma of APP/PS1 mice and found that long-term administration of LW-AFC ameliorated the secretion of 10 of these cytokines.…”

Section: Discussionmentioning

confidence: 50%

LW-AFC, a new formula derived from Liuwei Dihuang decoction, ameliorates behavioral and pathological deterioration via modulating the neuroendocrine-immune system in PrP-hAβPPswe/PS1ΔE9 transgenic mice

Wang¹,

Cheng³

et al. 2016

Alz Res Therapy

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BackgroundAccumulating evidence implicates the neuroendocrine immunomodulation (NIM) network in the physiopathological mechanism of Alzheimer’s disease (AD). Notably, we previously revealed that the NIM network is dysregulated in the PrP-hAβPPswe/PS1ΔE9 (APP/PS1) transgenic mouse model of AD.MethodsAfter treatment with a novel Liuwei Dihuang formula (LW-AFC), mice were cognitively evaluated in behavioral experiments. Neuron loss, amyloid-β (Aβ) deposition, and Aβ level were analyzed using Nissl staining, immunofluorescence, and an AlphaLISA assay, respectively. Multiplex bead analysis, a radioimmunoassay, immunochemiluminometry, and an enzyme-linked immunosorbent assay (ELISA) were used to measure cytokine and hormone levels. Lymphocyte subsets were detected using flow cytometry. Data between two groups were compared using a Student’s t test. Comparison of the data from multiple groups against one group was performed using a one-way analysis of variance (ANOVA) followed by a Dunnett’s post hoc test or a two-way repeated-measures analysis of variance with a Tukey multiple comparisons test.ResultsLW-AFC ameliorated the cognitive impairment observed in APP/PS1 mice, including the impairment of object recognition memory, spatial learning and memory, and active and passive avoidance. In addition, LW-AFC alleviated the neuron loss in the hippocampus, suppressed Aβ deposition in the brain, and reduced the concentration of Aβ1–42 in the hippocampus and plasma of APP/PS1 mice. LW-AFC treatment also significantly decreased the secretion of corticotropin-releasing hormone and gonadotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone in the pituitary. Moreover, LW-AFC increased CD8+CD28+ T cells, and reduced CD4+CD25+Foxp3+ T cells in the spleen lymphocytes, downregulated interleukin (IL)-1β, IL-2, IL-6, IL-23, granulocyte-macrophage colony stimulating factor, and tumor necrosis factor-α and -β, and upregulated IL-4 and granulocyte colony stimulating factor in the plasma of APP/PS1 mice.ConclusionsLW-AFC ameliorated the behavioral and pathological deterioration of APP/PS1 transgenic mice via the restoration of the NIM network to a greater extent than either memantine or donepezil, which supports the use of LW-AFC as a potential agent for AD therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0226-6) contains supplementary material, which is available to authorized users.

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“…Recent in vivo studies in animal models of AD demonstrated an ameliorating effect of CB2 receptor agonists on cognitive deficits in these mice that was associated with decreased microglial reactivity, reduced expression of pro-inflammatory cytokines [78, 79] and some decreases in Aβ accumulation after longer periods of treatments [79]. Genetic ablation of CB2 receptors in amyloid-producing mice resulted in opposing but significant effects on Aβ plaque load in different models [80, 81] indicating that effects of CB2 receptors is likely to depend of the stage of amyloidosis and other factors.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation

et al. 2015

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In Alzheimer’s disease (AD), one of the early responses to Aβ amyloidosis is recruitment of microglia to areas of new plaque. Microglial receptors such as cannabinoid receptor 2 (CB2) might be a suitable target for development of PET radiotracers that could serve as imaging biomarkers of Aβ-induced neuroinflammation. Mouse models of amyloidosis (J20APPswe/ind and APPswe/PS1ΔE9) were used to investigate the cellular distribution of CB2 receptors. Specificity of CB2 antibody (H60) was confirmed using J20APPswe/ind mice lacking CB2 receptors. APPswe/PS1ΔE9 mice were used in small animal PET with a CB2-targeting radiotracer, [11C]A836339. These studies revealed increased binding of [11C]A836339 in amyloid-bearing mice. Specificity of the PET signal was confirmed in a blockade study with a specific CB2 antagonist, AM630. Confocal microscopy revealed that CB2-receptor immunoreactivity was associated with astroglial (GFAP) and, predominantly, microglial (CD68) markers. CB2 receptors were observed, in particular, in microglial processes forming engulfment synapses with Aβ plaques. In contrast to glial cells, neuron (NeuN)-derived CB2 signal was equal between amyloid-bearing and control mice. The pattern of neuronal CB2 staining in amyloid-bearing mice was similar to that in human cases of AD. The data collected in this study indicate that Aβ amyloidosis without concomitant tau pathology is sufficient to activate CB2 receptors that are suitable as an imaging biomarker of neuroinflammation. The main source of enhanced CB2 PET binding in amyloid-bearing mice is increased CB2 immunoreactivity in activated microglia. The presence of CB2 immunoreactivity in neurons does not likely contribute to the enhanced CB2 PET signal in amyloid-bearing mice due to a lack of significant neuronal loss in this model. However, significant loss of neurons as seen at late stages of AD might decrease the CB2 PET signal due to loss of neuronally-derived CB2. Thus this study in mouse models of AD indicates that a CB2-specific radiotracer can be used as a biomarker of neuroinflammation in the early preclinical stages of AD, when no significant neuronal loss has yet developed.

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Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer's disease mouse model

Cited by 76 publications

References 22 publications

The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain

The multiplicity of spinal AA-5-HT anti-nociceptive action in a rat model of neuropathic pain

LW-AFC, a new formula derived from Liuwei Dihuang decoction, ameliorates behavioral and pathological deterioration via modulating the neuroendocrine-immune system in PrP-hAβPPswe/PS1ΔE9 transgenic mice

Cannabinoid CB2 Receptors in a Mouse Model of Aβ Amyloidosis: Immunohistochemical Analysis and Suitability as a PET Biomarker of Neuroinflammation

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