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The Journal of Neuroscience, October 19, 2005, 25(42):9686-9693; doi:10.1523/JNEUROSCI.2829-05.2005

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Neurobiology of Disease
Vulnerability of Dentate Granule Cells to Disruption of Arc Expression in Human Amyloid Precursor Protein Transgenic Mice

Jorge J. Palop,^1,2 Jeannie Chin,^1,2 Nga Bien-Ly,¹ Catherine Massaro,^1,3 Bertrand Z. Yeung,¹ Gui-Qiu Yu,¹ and Lennart Mucke^1,2,3

¹Gladstone Institute of Neurological Disease, ²Department of Neurology, and ³Neuroscience Graduate Program, University of California, San Francisco, San Francisco, California 94158

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- (A) 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 -actinin-2, which is located in dendritic spines and, like Arc, fulfills important functions in excitatory synaptic activity. Reductions in Arc and -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-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.

Key words: Alzheimer; dendritic spines; immediate-early gene; NMDA; novel environment; plasticity

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Received March 14, 2005; revised August 15, 2005; accepted August 17, 2005.

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