Title | Memory impairment in transgenic Alzheimer mice requires cellular prion protein. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Gimbel, DA, Nygaard, HB, Coffey, EE, Gunther, EC, Laurén, J, Gimbel, ZA, Strittmatter, SM |
Journal | J Neurosci |
Volume | 30 |
Issue | 18 |
Pagination | 6367-74 |
Date Published | 2010 May 5 |
ISSN | 1529-2401 |
Keywords | Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Avoidance Learning, Brain, Disease Models, Animal, Maze Learning, Memory, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Presenilin-1, PrPC Proteins, Random Allocation, Serotonin, Survival Analysis |
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). |
DOI | 10.1523/JNEUROSCI.0395-10.2010 |
Alternate Journal | J. Neurosci. |
PubMed ID | 20445063 |
PubMed Central ID | PMC3323924 |
Grant List | P30 DA018343 / DA / NIDA NIH HHS / United States R01 AG034924 / AG / NIA NIH HHS / United States R01 AG034924-01A1 / AG / NIA NIH HHS / United States R01 NS039962 / NS / NINDS NIH HHS / United States R01 NS039962-11 / NS / NINDS NIH HHS / United States R01 NS042304 / NS / NINDS NIH HHS / United States R01 NS042304-09 / NS / NINDS NIH HHS / United States R01 NS056485 / NS / NINDS NIH HHS / United States R37 NS033020 / NS / NINDS NIH HHS / United States R37 NS033020-19 / NS / NINDS NIH HHS / United States |