Comparison of the Amyloid Load in the Brains of Two Transgenic Alzheimer’s Disease Mouse Models Quantified by Florbetaben Positron Emission Tomography

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.

Impairment in novelty-promoted memory via behavioral tagging and capture before apparent memory loss in a knock-in model of Alzheimer’s disease

“…Collective evidence leads to the view that locus coeruleus and ventral tegmental area send projections to the hippocampus which enables novelty detection 46,57 and that such cross-region projections enable novelty-facilitated memory persistence through BTC 21,58 . Amyloid pathology is apparent in these midbrain structures in AD mouse models 59,60 and in App NL-G-F/NL-G-F mice 10,61,62 . Loss of dopaminergic neurons in midbrain is seen in familial AD mouse models with alpha-synuclein pathology 63 or presenilin mutations 60 .…”

Cryo-EM Structures of Amyloid-β Fibrils from Alzheimer’s Disease Mouse Models

“…Yet, [ 11 C]PiB does not work effectively in every mouse model, as is the case for the APP/PS1 model and interestingly, that model contains murine type III fibrils which are similar to those of human Arctic brain which is also PiB-negative [28]. Thus, it is believed that the ability of [ 11 C] PiB to detect pathology depends on differences in the structure of amyloid plaques and Aβ fibrils therein [46]- [49]. For example, it has been shown that the tg-APPArcSwe model exhibits higher [ 11 C]PiB binding that the APP NL-G-F model [50], whose purified Aβ structures differ from human type I and type II filaments.…”

“…For example, it has been shown that the tg-APPArcSwe model exhibits higher [ 11 C]PiB binding that the APP NL-G-F model [50], whose purified Aβ structures differ from human type I and type II filaments. Furthermore, a recent study that used the 18 F-labeled amyloid PET tracer florbetaben (FBB) to directly compare the APP/PS1 and the ARTE10 mouse models showed that the ARTE10 mice are more suitable for amyloid-PET due to their congophilic dense-cored plaques and overall higher plaque load compared to the APP/PS1 mouse model [49].…”

“…Brain tissue from the tg-APPSwe, tg-APPArcSwe, and the ARTE10 mouse models has been extensively characterized in previous studies [29], [49], [55], [58]- [60].…”

Estimating the synaptic density deficit in Alzheimer’s disease using multi-contrast CEST imaging

“…In this study, we used Glu-weighted and Cr-weighted endogenous CEST contrasts to map the synaptic deficit in the ARTE10 mouse model of AD [ 25 ]. In conjunction with 1 H-MRS and/or immunohistochemistry, Glu-CEST has previously been used in vitro and in vivo preclinical models of neurodegeneration [ 26 – 34 ].…”