Transcranialin vivodetection of amyloid-beta at single plaque resolution with large-field multifocal illumination fluorescence microscopy

Abstract

The abnormal deposition of beta-amyloid proteins in the brain is one of the major histopathological hallmarks of Alzheimer's disease. Currently available intravital microscopy techniques for highresolution plaque visualization commonly involve highly invasive procedures and are limited to a small field-of-view within the rodent brain. Here, we report the transcranial detection of amyloidbeta deposits at the whole brain scale with 20 m resolution in APP/PS1 and arcA mouse models of Alzheimer's disease amyloidosis using a large-field multifocal (LMI) fluorescence microscopy technique. Highly sensitive and specific detection of amyloid-beta deposits at a single plaque level in APP/PS1 and arcA mice was facilitated using luminescent conjugated oligothiophene HS-169.Immunohistochemical staining with HS-169, anti-A antibody 6E10, and conformation antibodies OC (fibrillar) of brain tissue sections further showed that HS-169 resolved compact parenchymal and vessel-associated amyloid deposits. The novel imaging platform offers new prospects for in vivo studies into Alzheimer's disease mechanisms in animal models as well as longitudinal monitoring of therapeutic responses at a single plaque level.

In-vitro and in-vivo characterization of CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of amyloid-beta deposits in Alzheimer mice

“…Developing tools for non-invasive detection of Aβ deposits at high-resolution in animal models of AD is critical for investigating disease mechanism and translational development of Aβ-targeted therapies. Most probes for Aβ including NIAD-4 [ 25 ], AOI-987 [ 26 ], BODIPY [ 27 ], THK-265 [ 28 ], DANIR [ [29] , [30] , [31] , [32] ], curcumin-derivatives CRANAD series [ 33 , 34 ], luminescent conjugated oligothiophenes [ 35 , 36 ] and DBA-SLOH [ 37 ] have been so far been designed for fluorescence imaging application. Nevertheless, Aβ binding fluorescent probes with suitable absorbance spectrum can be employed for OA imaging.…”

“…Progress is made not only in the development of optical instrumentation and reconstruction algorithms, but also in the design and synthesis of novel Aβ imaging probes [ 24 ]. For example, several probes have been reported for NIRF imaging including NIAD-4 [ 25 ], AOI-987 [ 26 ], BODIPY [ 27 ], THK-265 [ 28 ], DANIR [ [29] , [30] , [31] , [32] ], curcumin-derivatives CRANAD series [ 33 , 34 ], luminescent conjugated oligothiophenes [ 35 , 36 ] and DBA-SLOH [ 37 ]. NIRF imaging of Aβ deposits has been shown using a variety of AD mouse models [ 26 , [30] , [31] , [32] , [33] , [34] , 37 , 38 ].…”

Whole brain optoacoustic tomography reveals strain-specific regional beta-amyloid densities in Alzheimer’s disease amyloidosis models

“…The high degree of heterogeneity in the molecular architecture of misfolded Aβ observed in patients with AD may be related to the diversity of disease-associated mutations 62 . LCO has been applied to detect Aβ β-sheet structures in different animal models of AD amyloidosis 63, 64 and recognizing structural variants of Aβ fibrils from brain tissue from AD patients carrying different mutations 62, 65 . Yet the approach is not suited for in vivo applications.…”

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography

“…Recently, volumetric multi-spectral optoacoustic tomography (vMSOT) imaging has been shown to provide previously unavailable capabilities to visualize the bio-distribution of amyloid-β (Aβ) deposits in mouse models of AD amyloidosis (arcAβ and APP/PS1) [52][53][54] . vMSOT capitalizes on the high sensitivity of optical contrast and the high resolution provided by ultrasound 55,56 , and can attain penetration depth of the whole mouse brain.…”