Dataset Information

PET Imaging of Neutrophils Infiltration in Alzheimer's Disease Transgenic Mice.

ABSTRACT: Neutrophils are important components in the innate immune system. Neutrophil hyperactivation is regarded as a characteristic of Alzheimer's disease (AD). But in vivo imaging tools observing neutrophil activity in AD dynamically is lacking. This study aimed to identify neutrophil infiltration in AD transgenic mice. We used the AD triple-mutant transgenic mouse model and identified the genotype with RT-PCR. Behavioral experiments including an open-field test, a Morris water maze, and a Y-maze test were performed to evaluate the status of this AD model. ¹⁸F-AV45, ¹⁸F-PM-PBB3, ⁶⁸Ga-PEG-cFLFLFK, and ¹⁸F-DPA714 were synthesized according to previous reports. We employed microPET to detect tracer uptake in the AD model and the control mice at different stages. Western blotting was used to observe the expression of functional proteins. We proved the successful establishment of AD models by RT-PCR, behavioral tests, and ¹⁸F-AV45 and ¹⁸F-PM-PBB3 PET imaging. We found an increased neutrophil accumulation in the brains of the AD mice through ⁶⁸Ga-PEG-cFLFLFK PET imaging and Western blot assay. Our studies also demonstrated an elevated level of CAP37, which is produced by neutrophils, in the AD brain, and treatment with CAP37 promoted the expression of Iba1, iNOS, and COX-2 in BV2 cultures. Furthermore, our ¹⁸F-DPA714 PET imaging studies verified the raised activation of microglia in the brain of transgenic AD mice. Collectively, our findings indicate the increased activity of neutrophils in the brain and heart of AD model mice, ⁶⁸Ga-PEG-cFLFLFK PET imaging represents a sensitive method to observe the status of neutrophils in AD, and infiltrated neutrophils can induce the activation of microglia by releasing CAP37 and blocking the activity of neutrophils may be beneficial for the control of AD progression.

SUBMITTER: Kong Y

PROVIDER: S-EPMC7758535 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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PET Imaging of Neutrophils Infiltration in Alzheimer's Disease Transgenic Mice.

Kong Yanyan Y Liu Kawai K Hua Tao T Zhang Chencheng C Sun Bomin B Guan Yihui Y

Frontiers in neurology 20201210

Neutrophils are important components in the innate immune system. Neutrophil hyperactivation is regarded as a characteristic of Alzheimer's disease (AD). But <i>in vivo</i> imaging tools observing neutrophil activity in AD dynamically is lacking. This study aimed to identify neutrophil infiltration in AD transgenic mice. We used the AD triple-mutant transgenic mouse model and identified the genotype with RT-PCR. Behavioral experiments including an open-field test, a Morris water maze, and a Y-ma ...[more]

PMID: 33362678

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Project description:BackgroundMetabotropic glutamate subtype 5 receptors (mGluR5) modulate synaptic transmission and may constitute an important therapeutic target in Alzheimer's disease (AD) by mediating the synaptotoxic action of amyloid-β oligomers. We utilized the positron emission tomography (PET) radioligand [18F]FPEB to investigate mGluR5 binding in early AD.MethodsSixteen individuals with amnestic mild cognitive impairment (MCI) due to AD or mild AD dementia who were positive for brain amyloid were compared to 15 cognitively normal (CN) participants who were negative for brain amyloid. Diagnostic groups were well balanced for age, sex, and education. Dynamic PET scans were acquired for 60 min, starting at 60 min after the initial administration of up to 185 MBq of [18F]FPEB using a bolus-plus-constant-infusion method (Kbol = 190 min). Equilibrium modeling with a cerebellum reference region was used to estimate [18F]FPEB binding (BPND) to mGluR5. Analyses were performed with and without corrections for gray matter atrophy and partial volume effects.ResultsLinear mixed model analysis demonstrated a significant effect of group (p = 0.011) and the group × region interaction (p = 0.0049) on BPND. Post hoc comparisons revealed a significant reduction (43%) in mGluR5 binding in the hippocampus of AD (BPND = 0.76 ± 0.41) compared to CN (BPND = 1.34 ± 0.58, p = 0.003, unpaired t test) participants, and a nonsignificant trend for a reduction in a composite association cortical region in AD (BPND = 1.57 ± 0.25) compared to CN (BPND = 1.86 ± 0.63, p = 0.093) participants. Exploratory analyses suggested additional mGluR5 reductions in the entorhinal cortex and parahippocampal gyrus in the AD group. In the overall sample, hippocampal mGluR5 binding was associated with episodic memory scores and global function.Conclusions[18F]FPEB-PET revealed reductions in hippocampal mGluR5 binding in early AD. Quantification of mGluR5 binding in AD may expand our understanding of AD pathogenesis and accelerate the development of novel biomarkers and treatments.

Project description:Alzheimer's disease (AD) has an insidious onset and lacks clear early diagnostic markers, and by the time overt dementia symptoms appear, the disease is already in the mid-to-late stages. The search for early diagnostic markers of AD may open a critical window for Alzheimer's treatment and facilitate early intervention to slow the progression of AD. In this study, we aimed to explore the imaging markers for early diagnosis of AD through the combined application of structural magnetic resonance imaging (sMRI), resting-state functional magnetic resonance imaging (rs-fMRI), and 1H-magnetic resonance spectroscopy (1H-MRS) multimodal magnetic resonance imaging (MRI) techniques at the animal experimental level, with the aim to provide a certain reference for early clinical diagnosis of AD. First, sMRI scans were performed on 4-month-old amyloid beta precursor protein/presenilin 1 (APP/PS1) transgenic AD model mice and wild type mice of the same litter using a 7.0 T animal MRI scanner to analyze the differential brain regions with structural changes in the gray matter of the brain by voxel-based morphometry (VBM). Next, rs-fMRI scans were performed to analyze the differential brain regions between groups for local spontaneous brain activity and functional connectivity (FC) between brain regions. Finally, 1H-MRS scans were performed to quantify and analyze intergroup differences in the relative concentrations of different metabolites within regions of interest (cortex and hippocampus). Compared with wild type mice, the volume of the left hippocampus, and right olfactory bulb of APP/PS1 transgenic AD model mice were reduced, the functional activity of the bilateral hippocampus, right piriform cortex and right caudate putamen was reduced, the functional network connectivity of the hippocampus was impaired, and the relative content of N-acetylaspartate (NAA)in the hippocampus was decreased. In addition, this study found that imaging changes in olfactory-related brain regions were closely associated with AD diagnosis, and these findings may provide some reference for the early diagnosis of AD.

Dataset Information

PET Imaging of Neutrophils Infiltration in Alzheimer's Disease Transgenic Mice.

Publications

PET Imaging of Neutrophils Infiltration in Alzheimer's Disease Transgenic Mice.

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