Abstract
Alzheimer’s disease (AD) is characterized by formation of amyloid plaques and neurofibrillary tangles in the brain, which can be mimicked by transgenic mouse models. Here, we report on the characterization of amyloid load in the brains of two transgenic amyloidosis models using positron emission tomography (PET) with florbetaben (FBB), an 18F-labeled amyloid PET tracer routinely used in AD patients. Young, middle-aged, and old homozygous APP/PS1 mice (ARTE10), old hemizygous APPswe/PS1ΔE9, and old wild-type control mice were subjected to FBB PET using a small animal PET/computed tomography scanner. After PET, brains were excised, and ex vivo autoradiography was performed. Plaque pathology was verified on brain sections with histological methods. Amyloid plaque load increased progressively with age in the cortex and hippocampus of ARTE10 mice, which could be detected with both in vivo FBB PET and ex vivo autoradiography. FBB retention showed significant differences to wild-type controls already at 9 months of age by both in vivo and ex vivo analyses. An excellent correlation between data derived from PET and autoradiography could be obtained (rPearson = 0.947, p < 0.0001). Although amyloid load detected by FBB in the brains of old APPswe/PS1ΔE9 mice was as low as values obtained with young ARTE10 mice, statistically significant discrimination to wild-type animals was reached (p < 0.01). In comparison to amyloid burden quantified by histological analysis, FBB retention correlated best with total plaque load and number of congophilic plaques in the brains of both mouse models. In conclusion, the homozygous ARTE10 mouse model showed superior properties over APPswe/PS1ΔE9 mice for FBB small animal amyloid PET imaging. The absolute amount of congophilic dense-cored plaques seems to be the decisive factor for feasibility of amyloidosis models for amyloid PET analysis.
Highlights
Imaging of amyloid pathology in the brains of Alzheimer’s disease (AD) patients by means of positron emission tomography (PET), and specific radiotracers has been widely used in recent years and plays an important role as inclusion criteria in clinical trials (Villemagne et al, 2017)
ARTE10 mice of different ages were subjected to FBB PET in order to validate the ARTE10 mouse model concerning its suitability for amyloid PET imaging
Already in 9-monthold ARTE10 mice, and at all ages thereafter, the SUVRcb of FBB retention in the cortex was significantly different to wild-type controls (WT) animals
Summary
Imaging of amyloid pathology in the brains of Alzheimer’s disease (AD) patients by means of positron emission tomography (PET), and specific radiotracers has been widely used in recent years and plays an important role as inclusion criteria in clinical trials (Villemagne et al, 2017). The first PET tracer developed to bind to amyloid β (Aβ) plaques in AD patients’ brains was named Pittsburgh compound B ([11C]PiB). This 11C-labeled radiotracer has been shown to possess high affinity and selectivity to fibrillar Aβ in plaques and other Aβ–containing lesions (Cohen et al, 2012). Most mouse models concentrate on only one pathological hallmark of AD, that is, either amyloid or tau pathology This was achieved by transgenic expression of mutant genes responsible for early-onset familiar AD [e.g., mutated Aβ precursor protein (APP) and/or presenilin (PSEN)-1 or -2] or frontotemporal dementia (mutated microtubule-associated protein tau), respectively (Ameen-Ali et al, 2017). Accumulation of amyloid in the brains of the mice leads to the progressive deposition of amyloid plaques, dystrophic neurites and accompanying neuroinflammation and the development of cognitive and behavioral deficits upon aging (Ameen-Ali et al, 2017)
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