Asymmetry of Fibrillar Plaque Burden in Amyloid Mouse Models

Sacher, Christian; Blume, Tanja; Beyer, Leonie; Biechele, Gloria; Sauerbeck, Julia; Eckenweber, Florian; Deußing, Maximilian; Focke, Carola; Parhizkar, Samira; Lindner, Simon; Gildehaus, Franz-Josef; Ungern-Sternberg, Barbara von; Baumann, Karlheinz; Tahirović, Sabina; Kleinberger, Gernot; Willem, Michael; Haass, Christian; Bartenstein, Peter; Cumming, Paul; Rominger, Axel; Herms, Jochen; Brendel, Matthias

doi:10.2967/jnumed.120.242750

Cited by 23 publications

(16 citation statements)

References 29 publications

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“…López-Picón et al showed that [ 18 F]GE-180 signal reached plateaus at an early stage, while the Aβ load detected by [ 11 C]PIB was still increasing in APP23 mice ( 90 ). A recent study by Sacher et al showed an asymmetric pattern (hemispheric predominance) of Aβ load ([ 18 F]florbetaben) accompanied by microglial activation ([ 18 F]GE-180) in App NL-G-F knock-in mice ( 96 ). Increased levels of [ 18 F]GE-180 uptake indicative of microglial activation have been reported in patients with AD, semantic dementia, MCI, and four-repeat tauopathy compared to non-demented controls ( 88 – 91 ).…”

Section: Neuroinflammation Positron Emission Tomography Imagingmentioning

confidence: 99%

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Zhou

Kong

et al. 2021

Front. Immunol.

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Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer’s disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer’s disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer’s disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

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Section: Neuroinflammation Positron Emission Tomography Imagingmentioning

confidence: 99%

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Zhou

Kong

et al. 2021

Front. Immunol.

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“…Homozygotic App NL-G-F mice progressively exhibit widespread cerebral Aβ accumulation from 2 months of age [23,24]. Longitudinal 18 F-GE-180 data from 75 serial scans of homozygotic App NL-G-F mice imaged at four different ages (2.5, 5.0, 7.5, and 10 months) from previous [25,26] and unpublished studies were reprocessed. Six mice of each sex were imaged longitudinally at all four time-points whereas nine females entered PET imaging starting from 5.0 months of age.…”

Section: Animals and Study Designmentioning

confidence: 99%

Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases

Biechele

Franzmeier²,

Blume

et al. 2020

J Neuroinflammation

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Background In vivo assessment of neuroinflammation by 18-kDa translocator protein positron-emission-tomography (TSPO-PET) ligands receives growing interest in preclinical and clinical research of neurodegenerative disorders. Higher TSPO-PET binding as a surrogate for microglial activation in females has been reported for cognitively normal humans, but such effects have not yet been evaluated in rodent models of neurodegeneration and their controls. Thus, we aimed to investigate the impact of sex on microglial activation in amyloid and tau mouse models and wild-type controls. Methods TSPO-PET (18F-GE-180) data of C57Bl/6 (wild-type), AppNL-G-F (β-amyloid model), and P301S (tau model) mice was assessed longitudinally between 2 and 12 months of age. The AppNL-G-F group also underwent longitudinal β-amyloid-PET imaging (Aβ-PET; 18F-florbetaben). PET results were confirmed and validated by immunohistochemical investigation of microglial (Iba-1, CD68), astrocytic (GFAP), and tau (AT8) markers. Findings in cerebral cortex were compared by sex using linear mixed models for PET data and analysis of variance for immunohistochemistry. Results Wild-type mice showed an increased TSPO-PET signal over time (female +23%, male +4%), with a significant sex × age interaction (T = − 4.171, p < 0.001). The Aβ model AppNL-G-F mice also showed a significant sex × age interaction (T = − 2.953, p = 0.0048), where cortical TSPO-PET values increased by 31% in female AppNL-G-F mice, versus only 6% in the male mice group from 2.5 to 10 months of age. Immunohistochemistry for the microglial markers Iba-1 and CD68 confirmed the TSPO-PET findings in male and female mice aged 10 months. Aβ-PET in the same AppNL-G-F mice indicated no significant sex × age interaction (T = 0.425, p = 0.673). The P301S tau model showed strong cortical increases of TSPO-PET from 2 to 8.5 months of age (female + 32%, male + 36%), without any significant sex × age interaction (T = − 0.671, p = 0.504), and no sex differences in Iba-1, CD68, or AT8 immunohistochemistry. Conclusion Female mice indicate sex-dependent microglia activation in aging and in response to amyloidosis but not in response to tau pathology. This calls for consideration of sex difference in TSPO-PET studies of microglial activation in mouse models of neurodegeneration and by extension in human studies.

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“…The use of other radioactive tracers mainly F18 tracers, like florbetapir, flutemetanol or florbetaben, have allowed one to find a good correlation between, for example, florbetapir images and cortical amyloid pathology or to differentiate areas with frequent plaques from those containing sparse plaques [ 58 ]. Additionally, PET analysis can be used to look for asymmetries of Aβ-fibrillary plaques burden, an asymmetry, that could be associated with microglia activation in AD or in mouse models, for the disease [ 59 ].…”

Section: Resultsmentioning

confidence: 99%

Protein Biomarkers for the Diagnosis of Alzheimer’s Disease at Different Stages of Neurodegeneration

Pérez

Hernández

Ávila

2020

IJMS

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Mainly obtained from familial Alzheimer’s disease patients’ data, we know that some features of the neurodegenerative start several years before the appearance of clinical symptoms. In this brief review, we comment on some molecular and cellular markers appearing at different stages of the disease, before or once the clinical symptoms are evident. These markers are present in biological fluids or could be identified by image techniques. The combined use of molecular and cellular markers will be of interest to determine the development of the different phases of the disease.

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Asymmetry of Fibrillar Plaque Burden in Amyloid Mouse Models

Cited by 23 publications

References 29 publications

PET Imaging of Neuroinflammation in Alzheimer’s Disease

PET Imaging of Neuroinflammation in Alzheimer’s Disease

Glial activation is moderated by sex in response to amyloidosis but not to tau pathology in mouse models of neurodegenerative diseases

Protein Biomarkers for the Diagnosis of Alzheimer’s Disease at Different Stages of Neurodegeneration

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