Multiscale optical and optoacoustic imaging of amyloid-β deposits in mice

Abstract

Deposits of amyloid-β (Aβ) in the brains of rodents can be analysed by invasive intravital microscopy on a submillimetre scale, or via whole-brain images from modalities lacking the resolution or molecular specificity to accurately characterize Aβ pathologies. Here we show that large-field multifocal illumination fluorescence microscopy and panoramic volumetric multispectral optoacoustic tomography can be combined to longitudinally assess Aβ deposits in transgenic mouse models of Alzheimer's disease. We used fluorescent Aβ-targeted probes (the luminescent conjugated oligothiophene HS-169 and the oxazine-derivative AOI987) to transcranially detect Aβ deposits in the cortex of APP/PS1 and arcAβ mice with single-plaque resolution (8 μm) and across the whole brain (including the hippocampus and the thalamus, which are inaccessible by conventional intravital microscopy) at sub-150 μm resolutions. Two-photon microscopy, light-sheet microscopy and immunohistochemistry of brain-tissue sections confirmed the specificity and regional distributions of the deposits. High-resolution multiscale optical and optoacoustic imaging of Aβ deposits across the entire brain in rodents thus facilitates the in vivo study of Aβ accumulation by brain region and by animal age and strain.

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, 4-repeat/full-length tau and alpha-synuclein

“…We observed different association and/or dissociation constants and affinities of small molecules towards immobilized Aβ 42 , K18, full-length tau and αSyn fibrils by SPR. The k on and k off values fit with the observation of slow wash-out features of HS-169 and HS-84 reported in vivo (Calvo-Rodriguez et al, 2019b; Ni et al, 2022; Ni et al, 2020).…”

“…All sections spanning the complete rostro-caudal extent of the brain were kept in the correct order and stored at 4 °C in cryoprotect-solution (1:1:3 volume ratio of ethylenglycol, glycerol and 0.1 M PBS) until further processing (Henrich et al, 2018). Anti-αSyn pS129 antibodies, anti-phospho-tau antibodies (AT-8, AT-100), or anti-Aβ 1-16 antibody 6E10, plus fluorescent secondary antibody were used as previously described on brain slices from αSyn PFF-injected mice, arcAβ mice (Ni et al, 2022), and pR5 mice (Vagenknecht et al, 2022). Ligands were incubated after secondary antibody for 30 min.…”

Evaluation of CB2R expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

“…Twenty transgenic arcAβ mice overexpressing the human APP695 transgene containing the Swedish (K670N/M671L) and Arctic (E693G) mutations under control of the prion protein promoter at 6, 17, and 24 months of age and 20 age-matched nontransgenic littermates (NTLs) of both sexes were used in this study [33,23,37]. The arcAβ mouse model exhibits parenchymal plaque as well as cerebral amyloid angiopathy and shows impaired cerebrovascular functions [38,41].…”

Automatic analysis of skull thickness, scalp-to-cortex distance and association with age and sex in cognitively normal elderly

“…Skull shape abnormalities in ischemic cerebrovascular and mental diseases in adults have also been reported [10]. Optimization of the probe location on the head for neuroimaging/brain simulation thus has added value in various neurostimulation and imaging studies, such as simulation ultrasonic wave propagation and acoustic transmission [11][12][13][14][15][16].…”