P1-067: Relative impact of vascular versus parenchymal amyloid on synaptic plasticity-related gene induction

Abstract

Alzheimer's disease is characterized by numerous pathological abnormalities including amyloid deposition in the parenchyma and the vasculature. Transgenic mice replicating distinct aspects of Alzheimer pathology are useful models to evaluate contributions of these factors to cognitive decline. Investigate the relative impact of parenchymal versus vascular amyloid on synaptic plasticity–related gene induction. Three different mouse models of amyloidosis were used: a model which exhibits almost exclusively vascular amyloid (APPDutch), one which shows predominantly parenchymal amyloid (APPPS1), and one with a combination of parenchymal and vascular amyloid (APP23). The behavioral induction of Arc (activity–regulated cytoskeleton–associated protein), an effector immediate early gene known to be necessary for memory consolidation and learning was detected via fluorescent in–situ hybridization (ISH). Thus, the functional status of individual neurons and neural systems could be measured following the exploration of a novel environment. The number of Arc positive cells within the neocortex and dentate gyrus was quantified using stereological analysis. Radioactive ISH was also performed to compare relative levels of Arc mRNA. The pattern of activated, Arc mRNA positive cells was clearly disrupted in mice with parenchymal amyloid, while such obvious changes were not observed in vascular–depositing mice. Stereological analysis revealed a decrease in the percentage of Arc positive cells within the neocortex of mice with vascular (∼17%) or parenchymal (∼26%) amyloid compared to aged–matched controls. Interestingly, these reductions were even more pronounced in the dentate gyrus (∼51%; ∼58%), a region critical for relational memory. Taken together, our data indicate that both parenchymal and vascular amyloid impair the induction of an important learning–related gene, suggesting that both pathologies contribute to memory impairment in Alzheimer's disease.