Transcranial detection of amyloid‐beta at single plaque resolution in vivo with large‐field multifocal illumination fluorescence microscopy

Abstract

Background 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 high‐resolution plaque visualization commonly involve highly invasive procedures and are limited to small field‐of‐views within the rodent brain. Method We devised a large‐field multi‐focal illumination (LMI) fluorescence microscopy method that provides a 20 × 20 mm field‐of‐view and an axial resolution of ∼15 mm. In vivo and ex vivo transcranial LMI fluorescence microscopy and wide‐field fluorescence microscopy for amyloid deposits were performed in APP/PS1 and arcAb mouse models of Alzheimer’s disease amyloidosis using luminescent conjugated oligothiophene probe HS‐169. Immunohistochemical staining with HS‐169, anti‐Ab antibody 6E10, and conformation antibodies OC (fibrillar) of brain tissue sections Result LMI fluorescence microscopy detected amyloid‐beta deposits at a single plaque level in APP/PS1 and arcAb mice with high sensitivity and specificity. The contrast‐to‐noise ratio was approximately 24 times higher in LMI fluorescence microscopy of amyloid deposits compared to wide‐field fluorescence microscopy. Immunohistochemical staining showed HS‐169 co‐localized with 6E10 and OC stained compact parenchymal and vessel‐associated amyloid deposits. Conclusion The novel LMI in vivo amyloid imaging platform offers new prospects for studies into Alzheimer’s disease mechanisms in animal models as well as longitudinal monitoring of therapeutic responses at a single plaque level.

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

“…The advantage of MRI molecular imaging stems from its superior resolution and improved signal-to-noise ratio, enabled by the development in high-field MRI and coil arrays. MRI provides versatile functional, structural, and molecular readouts and longitudinal, large field-of-view imaging capacity compared to other imaging modalities, such as two-photon microscopy, fluorescence molecular tomography, and optoacoustic microscopy [ 225 , 226 , 227 , 228 , 229 , 230 ]. The disadvantages and limitations of preclinical MRI methods include the following:…”