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

Abstract

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.

P1–100: CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease

“…These results are consistent with the important role of reduced expression of proteins, such as NR2B and GluR1, in synaptic plasticity in transgenic mice (5). Aβ accumulation also has been shown to alter other transduction pathways involved in learning and memory (3,(6)(7)(8)(9).…”

Apolipoprotein E4 domain interaction: Synaptic and cognitive deficits in mice

“…These differences do not reflect reduced exploration of the novel environment by Arg-61 apoE mice, since no differences in exploratory behaviors or locomotion were seen in the elevated plus maze or open field test (see supplement data). We also noted that, in hippocampal CA1 strata radiatum, Arc-immunoreactivities in the dendrites of CA1 pyramidal neurons were higher in both non-stimulated and novel environment-stimulated WT mice than those of Arg-61 apoE mice ( Figure 5A), however as discussed by Palop et al [22], the quantification of Arc-mRNA expression more accurately reflects the novel environment-induced Arc expression in dendrites.…”

Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease

“…By binding integrins, Reelin enhances the expression of the activityregulated cytoskeletal protein Arc (Dong et al, 2003), which is critical for LTP maintenance and memory consolidation (Guzowski et al, 2000;McIntyre et al, 2005;Plath et al, 2006;Tzingounis and Nicoll, 2006). Interestingly, hAPP FAD mice have decreased hippocampal levels of Arc and phosphorylated NR2B, as well as LTP reductions and memory impairments (Chapman et al, 1999;Palop et al, 2003Palop et al, , 2005Chin et al, 2005;Kobayashi and Chen, 2005). The current study raises the possibility that decreased levels of Reelin in the entorhinal cortex and hippocampus of hAPP FAD mice may underlie or exacerbate their deficits in hippocampal NMDA receptor-dependent signaling, synaptic plasticity, and related cognitive functions.…”