Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 42, Pages 9686-9693Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2829-05.2005
Keywords
Alzheimer; dendritic spines; immediate-early gene; NMDA; novel environment; plasticity
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Funding
- NIA NIH HHS [AG022074, AG11385, P01 AG022074, P50 AG023501, AG023501, R37 AG011385, R01 AG011385] Funding Source: Medline
- NINDS NIH HHS [R01 NS041787, NS41787] Funding Source: Medline
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Activity-induced expression of Arc is necessary for maintenance of long-term potentiation and for memory consolidation. In transgenic (TG) mice with neuronal production of human amyloid precursor protein (hAPP) and hAPP-derived amyloid-beta (A beta) peptides, basal Arc expression was reduced primarily in granule cells of the dentate gyrus. After exploration of a novel environment, Arc expression in these neurons was unaltered in hAPP mice but increased markedly in nontransgenic controls. Other TG neuronal populations showed no or only minor deficits in Arc expression, indicating a special vulnerability of dentate granule cells. The phosphorylation states of NR2B and ERK1/2 were reduced in the dentate gyrus of hAPP mice, suggesting attenuated activity in NMDA-dependent signaling pathways that regulate synaptic plasticity as well as Arc expression. Arc reductions in hAPP mice correlated with reductions in the actin-binding protein alpha-actinin-2, which is located in dendritic spines and, like Arc, fulfills important functions in excitatory synaptic activity. Reductions in Arc and alpha-actinin-2 correlated tightly with reductions in Fos and calbindin, shown previously to reflect learning deficits in hAPP mice. None of these alterations correlated with the extent of plaque formation, suggesting a plaque-independent mechanism of hAPP/A beta-induced neuronal deficits. The brain region-specific depletion of factors that participate in activity-dependent modification of synapses may critically contribute to cognitive deficits in hAPP mice and possibly in humans with Alzheimer's disease.
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