title: Memory impairment in transgenic Alzheimer mice requires cellular prion protein.
abstract: Soluble oligomers of the amyloid-beta (Abeta) peptide are thought to play a key role in the pathophysiology of Alzheimer's disease (AD). Recently, we reported that synthetic Abeta oligomers bind to cellular prion protein (PrP(C)) and that this interaction is required for suppression of synaptic plasticity in hippocampal slices by oligomeric Abeta peptide. We hypothesized that PrP(C) is essential for the ability of brain-derived Abeta to suppress cognitive function. Here, we crossed familial AD transgenes encoding APPswe and PSen1DeltaE9 into Prnp-/- mice to examine the necessity of PrP(C) for AD-related phenotypes. Neither APP expression nor Abeta level is altered by PrP(C) absence in this transgenic AD model, and astrogliosis is unchanged. However, deletion of PrP(C) expression rescues 5-HT axonal degeneration, loss of synaptic markers, and early death in APPswe/PSen1DeltaE9 transgenic mice. The AD transgenic mice with intact PrP(C) expression exhibit deficits in spatial learning and memory. Mice lacking PrP(C), but containing Abeta plaque derived from APPswe/PSen1DeltaE9 transgenes, show no detectable impairment of spatial learning and memory. Thus, deletion of PrP(C) expression dissociates Abeta accumulation from behavioral impairment in these AD mice, with the cognitive deficits selectively requiring PrP(C).
authors.affiliation: Cellular Neuroscience, Neurodegeneration, and Repair Program, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Gimbel
authors.forename: Haakon B
authors.initials: HB
authors.lastname: Nygaard
authors.forename: Erin E
authors.initials: EE
authors.lastname: Coffey
authors.forename: Erik C
authors.initials: EC
authors.lastname: Gunther
authors.forename: Juha
authors.initials: J
authors.lastname: Laurén
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Gimbel
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001362:Avoidance Learning; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018782:Maze Learning; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics*; D018621:PrPC Proteins / Q000235:genetics / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics; D011897:Random Allocation; D012701:Serotonin / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018621:PrPC Proteins; D053764:Presenilin-1; D012701:Serotonin
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