Abstract
Reelin is a large extracellular glycoprotein required for proper neuronal positioning during development. In the adult brain, Reelin plays a crucial modulatory role in the induction of synaptic plasticity and successful formation of long-term memory. Recently, alterations in Reelin-mediated signaling have been suggested to contribute to neuronal dysfunction associated with Alzheimer's disease (AD). We previously reported that aging in several species is characterized by a decline in Reelin-expressing interneurons and concomitant accumulation in amyloid-like plaques in the hippocampal formation, significantly correlating with cognitive impairments. In transgenic AD mice, we detected Reelin in oligomeric amyloid-beta aggregates and in tight association with fibrillary plaques. Here, we used immunohistochemistry at the light and electron microscopy level to characterize further the morphology, temporal and spatial progression, as well as the potential of Reelin-positive plaques to sequester murine amyloid-beta peptides in wild-type mice across aging. We developed a new immunohistochemical protocol involving a stringent protease pretreatment which markedly enhanced Reelin-immunoreactivity and allowed specific detection of variable shapes of murine anti-amyloid-beta protein precursor-immunoreactivity in plaques in the hippocampus, likely representing N-terminal fragments and amyloid-beta species. Ultrastructural investigations confirmed the presence of Reelin in extracellular space, somata of interneurons in young and aged wild-type mice. In aged mice, Reelin- and amyloid-beta-immunoreactivity was detected in extracellular, spherical deposits, likely representing small intermediates or fragments of amyloid fibrils. Our results suggest that Reelin itself aggregates into abnormal oligomeric or protofibrillary deposits during aging, potentially creating a precursor condition for fibrillary amyloid-beta plaque formation.
Doehner, J