Cerebral [beta]-Amyloidosis in Mice Investigated by Ultramicroscopy

• Published in: PloS one 2015-05, Vol.10 (5)
• Main Authors: Jährling, Nina, Becker, Klaus, Wegenast-Braun, Bettina M, Grathwohl, Stefan A, Jucker, Mathias, Dodt, Hans-Ulrich
• Format: Article
• Language: English
• Subjects: Amyloid beta-protein; Amyloidosis; Diagnosis; Microscopy; Physiological aspects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0125418

Alzheimer's disease (AD) is the most common neurodegenerative disorder. AD neuropathology is characterized by intracellular neurofibrillary tangles and extracellular [beta]-amyloid deposits in the brain. To elucidate the complexity of AD pathogenesis a variety of transgenic mouse models have been generated. An ideal imaging system for monitoring [beta]-amyloid plaque deposition in the brain of these animals should allow 3D-reconstructions of [beta]-amyloid plaques via a single scan of an uncropped brain. Ultramicroscopy makes this possible by replacing mechanical slicing in standard histology by optical sectioning. It allows a time efficient analysis of the amyloid plaque distribution in the entire mouse brain with 3D cellular resolution. We herein labeled [beta]-amyloid deposits in a transgenic mouse model of cerebral [beta]-amyloidosis (APPPS1 transgenic mice) with two intraperitoneal injections of the amyloid-binding fluorescent dye methoxy-X04. Upon postmortem analysis the total number of [beta]-amyloid plaques, the [beta]-amyloid load (volume percent) and the amyloid plaque size distributions were measured in the frontal cortex of two age groups (2.5 versus 7-8.5 month old mice). Applying ultramicroscopy we found in a proof-of-principle study that the number of [beta]-amyloid plaques increases with age. In our experiments we further observed an increase of large plaques in the older age group of mice. We demonstrate that ultramicroscopy is a fast, and accurate analysis technique for studying [beta]-amyloid lesions in transgenic mice allowing the 3D staging of [beta]-amyloid plaque development. This in turn is the basis to study neural network degeneration upon cerebral [beta]-amyloidosis and to assess A[beta] -targeting therapeutics.