High-resolution 3D reconstruction reveals intra-synaptic amyloid fibrils.

ABSTRACT: ?-Amyloid (A?) accumulation and aggregation are hallmarks of Alzheimer's disease (AD). High-resolution three-dimensional (HR-3D) volumetric imaging allows for better analysis of fluorescence confocal microscopy and 3D visualization of A? pathology in brain. Early intraneuronal A? pathology was studied in AD transgenic mouse brains by HR-3D volumetric imaging. To better visualize and analyze the development of A? pathology, thioflavin S staining and immunofluorescence using antibodies against A?, fibrillar A?, and structural and synaptic neuronal proteins were performed in the brain tissue of Tg19959, wild-type, and Tg19959-YFP mice at different ages. Images obtained by confocal microscopy were reconstructed into three-dimensional volumetric datasets. Such volumetric imaging of CA1 hippocampus of AD transgenic mice showed intraneuronal onset of A?42 accumulation and fibrillization within cell bodies, neurites, and synapses before plaque formation. Notably, early fibrillar A? was evident within individual synaptic compartments, where it was associated with abnormal morphology. In dendrites, increasing intraneuronal thioflavin S correlated with decreases in neurofilament marker SMI32. Fibrillar A? aggregates could be seen piercing the cell membrane. These data support that A? fibrillization begins within AD vulnerable neurons, leading to disruption of cytoarchitecture and degeneration of spines and neurites. Thus, HR-3D volumetric image analysis allows for better visualization of intraneuronal A? pathology and provides new insights into plaque formation in AD.

SUBMITTER: Capetillo-Zarate E 

PROVIDER: S-EPMC3204026 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature