title: Independent effects of intra- and extracellular Abeta on learning-related gene expression.
abstract: Alzheimer's disease is characterized by numerous pathological abnormalities, including amyloid beta (Abeta) deposition in the brain parenchyma and vasculature. In addition, intracellular Abeta accumulation may affect neuronal viability and function. In this study, we evaluated the effects of different forms of Abeta 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 controlled 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 14 to 26%), indicating an impairment in neuronal encoding and network activation. Young APPDutch and APP23 mice exhibited intracellular, granular Abeta staining that was most prominent in the large pyramidal cells of cortical layer V; these animals also had reductions in levels of Arc. 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 Abeta in young mice, as independent factors that contribute to reduced Arc levels. These results provide evidence that two independent Abeta pathologies converge in their impact on cognitive function in Alzheimer's disease.
authors: Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, Germany.
authors: Bettina M
authors: BM
authors: Wegenast-Braun
authors: Ana
authors: A
authors: Fulgencio Maisch
authors: Daniel
authors: D
authors: Eicke
authors: Rebecca
authors: R
authors: Radde
authors: Martin C
authors: MC
authors: Herzig
authors: Matthias
authors: M
authors: Staufenbiel
authors: Mathias
authors: M
authors: Jucker
authors: Michael E
authors: ME
authors: Calhoun
mesh_terms: D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003593:Cytoplasm / Q000737:chemistry; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005109:Extracellular Matrix; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007858:Learning / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C092069:activity regulated cytoskeletal-associated protein