Regional Differences in Reactive Gliosis Induced by Substrate-Bound β-Amyloid

Abstract

Regions of gliosis surround deposits of (β-amyloid peptide (βAP) in senile plaques of Alzheimer's disease (AD). The association between reactive astrocytes and βAP in senile plaques is most pronounced in cortex and hippocampus but not at other anatomical sites of βAP deposition. We hypothesized that this region-specific pathology in AD could be attributed to differences in glial reactivity in different parts of the central nervous system (CNS). To test this hypothesis, we assayed astrocytes from cerebral cortex, hippocampus, cerebellum, and spinal cord for cellular responsiveness to substrate-bound βAP in vitro. Astrocyte reactivity was monitored by morphological changes, increased deposition of chondroitin sulfate proteoglycan-containing matrix, and alterations in proteoglycan metabolism. Based on these criteria, only cortical and hippocampal astrocytes showed marked reactivity to immobilized βAP. In cortical and hippocampal cultures only, immobilized βAP resulted in increased total radiosulfate incorporation into proteoglycans which was mainly found in the cell/matrix rather than in the media-associated compartment. There were also differences in the proteoglycan synthesis patterns of astrocyte cultures isolated from these CNS regions. These findings suggest that (1) astrocytes are regionally heterogenous in their reactive response to βAP and (2) that specific molecules, in addition to βAP, may exist following trauma or disease which trigger reactive states in astroglia in the cerebellum or spinal cord. These local differences in the interaction between βAP and surrounding astrocytes may play a role in the region-specific pathogenesis of Alzheimer's disease.