Independent Effects of Intra- and Extracellular Aβ on Learning-Related Gene Expression

Alzheimer's disease is characterized by numerous pathological abnormalities, including amyloid beta (A beta) deposition in the brain parenchyma and vasculature. In addition, intracellular A beta accumulation may affect neuronal viability and function. In this study, we evaluated the effects of different forms of A beta on cognitive decline by analyzing the behavioral induction of the learning-related gene Arc/Arg3.1 in three different transgenic mouse models of cerebral amyloidosis (APPPS1, APPDutch, and APP23). Following a con trolled spatial exploration paradigm, reductions in both the number of Arc-activated neurons and the levels of Arc mRNA were seen in the neocortices of depositing mice from all transgenic lines (deficits ranging from 1.4 to 26%), indicating an impairment in neuronal encoding and network activation. Young APPDutch and APP23 mice exhibited intracellular, granular A beta staining that was most prominent in the large pyramidal cells of cortical layer V; these animals also had reductions in levels of Are. In the dentate gyrus, striking reductions (up to 58% in aged APPPS1 mice) in the number of Arc-activated cells were found. Single-cell analyses revealed both the proximity to fibrillar amyloid in aged mice, and the transient presence of intracellular granular A beta in young mice, as independent factors that contribute to reduced Arc levels. These results provide evidence that two independent A beta pathologies converge in their impact on cognitive function in Alzheimer's disease. (Am Pathol 2009, 175:271-282; DOI: 10.2353/ajpath.2009.090044)