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FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders.

ABSTRACT: The adult hippocampus plays a central role in memory formation, synaptic plasticity, and neurogenesis. The subgranular zone of the dentate gyrus contains neural progenitor cells with self-renewal and multilineage potency. Transgene expression of familial Alzheimer's disease-linked mutants of ?-amyloid precursor protein (APP) and presenilin-1 leads to a significant inhibition of neurogenesis, which is potentially linked to age-dependent memory loss. To investigate the effect of neurogenesis on cognitive function in a relevant disease model, FGF2 gene is delivered bilaterally to the hippocampi of APP+presenilin-1 bigenic mice via an adenoassociated virus serotype 2/1 hybrid (AAV2/1-FGF2). Animals injected with AAV2/1-FGF2 at a pre- or postsymptomatic stage show significantly improved spatial learning in the radial arm water maze test. A neuropathological investigation demonstrates that AAV2/1-FGF2 injection enhances the number of doublecortin, BrdU/NeuN, and c-fos-positive cells in the dentate gyrus, and the clearance of fibrillar amyloid-? peptide (A?) in the hippocampus. AAV2/1-FGF2 injection also enhances long-term potentiation in another APP mouse model (J20) compared with control AAV2/1-GFP-injected littermates. An in vitro study confirmed the enhanced neurogenesis of mouse neural stem cells by direct AAV2/1-FGF2 infection in an A? oligomer-sensitive manner. Further, FGF2 enhances A? phagocytosis in primary cultured microglia, and reduces A? production from primary cultured neurons after AAV2/1-FGF2 infection. Thus, our data indicate that virus-mediated FGF2 gene delivery has potential as an alternative therapy of Alzheimer's disease and possibly other neurocognitive disorders.

SUBMITTER: Kiyota T

PROVIDER: S-EPMC3241747 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders.

Kiyota Tomomi T Ingraham Kaitlin L KL Jacobsen Michael T MT Xiong Huangui H Ikezu Tsuneya T

Proceedings of the National Academy of Sciences of the United States of America 20111031 49

The adult hippocampus plays a central role in memory formation, synaptic plasticity, and neurogenesis. The subgranular zone of the dentate gyrus contains neural progenitor cells with self-renewal and multilineage potency. Transgene expression of familial Alzheimer's disease-linked mutants of β-amyloid precursor protein (APP) and presenilin-1 leads to a significant inhibition of neurogenesis, which is potentially linked to age-dependent memory loss. To investigate the effect of neurogenesis on co ...[more]

PMID: 22042871

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Project description:BackgroundSeveral studies indicate general anesthetics can produce lasting effects on cognitive function. The commonly utilized anesthetic agent Sevoflurane has been implicated in neurodegenerative processes. The present study aimed to identify molecular underpinnings of Sevoflurane anesthesia linked neurocognitive changes by leveraging publically available datasets for bioinformatics analysis.MethodsA Sevoflurane anesthesia related gene expression dataset was obtained. Sevoflurane related genes were obtained from the CTD database. Neurocognitive disorders (NCD) related genes were downloaded from DisGeNET and CTD. Intersecting differentially expressed genes between Sevoflurane and NCD were identified as cross-talk genes. A protein-protein interaction (PPI) network was constructed. Hub genes were selected using LASSO regression. Single sample gene set enrichment analysis; functional network analysis, pathway correlations, composite network analysis and drug sensitivity analysis were performed.ResultsFourteen intersecting cross-talk genes potentially were identified. These were mainly involved in biological processes including peptidyl-serine phosphorylation, cellular response to starvation, and response to gamma radiation, regulation of p53 signaling pathway, AGE-RAGE signaling pathway and FoxO signaling. Egr1 showed a central role in the PPI network. Cdkn1a, Egr1, Gadd45a, Slc2a1, and Slc3a2 were identified as important or hub cross-talk genes. Among the interacting pathways, Interleukin-10 signaling and NF-kappa B signaling enriched among Sevoflurane-related DEGs were highly correlated with HIF-1 signaling enriched in NCD-related genes. Composite network analysis showed Egr1 interacted with AGE-RAGE signaling and Apelin signaling pathways, Cdkn1a, and Gadd45a. Cdkn1a was implicated in in FoxO signaling, PI3K-Akt signaling, ErbB signaling, and Oxytocin signaling pathways, and Gadd45a. Gadd45a was involved in NF-kappa B signaling and FoxO signaling pathways. Drug sensitivity analysis showed Egr1 was highly sensitive to GENIPIN.ConclusionA suite of bioinformatics analysis revealed several key candidate hippocampal genes and associated functional signaling pathways that could underlie Sevoflurane associated neurodegenerative processes.

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Dataset Information

FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders.

Publications

FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders.

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