Farnesyltransferase Haplodeficiency Reduces Neuropathology and Rescues Cognitive Function in a Mouse Model of Alzheimer Disease

Cheng, Shaowu; Cao, Dongfeng; Hottman, David A.; Yuan, Long; Bergö, Martin O.; Li, Ling

doi:10.1074/jbc.m113.503904

Cited by 40 publications

(60 citation statements)

References 48 publications

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“…If this is true, we would expect statins to protect cognitive decline by decreasing the amount of farnesylated or geranylgeranylated proteins. This hypothesis is consistent with studies showing that statins enhance long-term potentiation [48], and demonstrating that decreasing prenyltransferases like farnesyl transferase ameliorate cognitive decline in a mouse model of Alzheimer’s disease [49]. It will be interesting to learn whether similar results are seen with geranylgeranyl transferase inhibitors.…”

Section: Discussionsupporting

confidence: 85%

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Inhibiting Geranylgeranylation Increases Neurite Branching and Differentially Activates Cofilin in Cell Bodies and Growth Cones

Samuel

Reddy²,

Kaimal³

et al. 2014

Mol Neurobiol

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Inhibitors of the mevalonate pathway, including the highly prescribed statins, reduce the production of cholesterol and isoprenoids such as geranylgeranyl pyrophosphates. The Rho family of small guanine triphosphatases (GTPases) requires isoprenylation, specifically geranylgeranylation, for activation. Because Rho GTPases are primary regulators of actin filament rearrangements required for process extension, neurite arborization and synaptic plasticity, statins may affect cognition or recovery from nervous system injury. Here, we assessed how manipulating geranylgeranylation affects neurite initiation, elongation and branching in neuroblastoma growth cones. Treatment with the statin, lovastatin (20 μM) decreased measures of neurite initiation by 17.0% to 19.0% when a source of cholesterol was present and increased neurite branching by 4.03 to 9.54 fold (regardless of exogenous cholesterol). Neurite elongation was increased by treatment with lovastatin only in cholesterol-free culture conditions. Treatment with lovastatin decreased growth cone actin filament content by up to 24.3%. In all cases, co-treatment with the prenylation precursor, geranylgeraniol (10 μM), reversed the effect of lovastatin. In prior work, statin effects on outgrowth were linked to modulating the actin depolymerizing factor, cofilin. In our assays, treatment with lovastatin or geranylgeraniol decreased cofilin phosphorylation in whole cell lysates. However, lovastatin increased cofilin phosphorylation in cell bodies and decreased it in growth cones, indicating differential regulation in specific cell regions. Together, we interpret these data to suggest that protein geranylgeranylation likely regulates growth cone actin filament content and subsequent neurite outgrowth through mechanisms that also affect actin nucleation and polymerization.

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Section: Discussionsupporting

confidence: 85%

“…While some of the effects are related to decreased cholesterol [47], there is good evidence that the decrease in protein isoprenylation may also play an important role [46,48,49]. Our data suggest that statins increase neurite arborization, an aspect of neurite outgrowth that likely correlates with increased synaptic plasticity.…”

Section: Discussionmentioning

confidence: 60%

Inhibiting Geranylgeranylation Increases Neurite Branching and Differentially Activates Cofilin in Cell Bodies and Growth Cones

Samuel

Reddy²,

Kaimal³

et al. 2014

Mol Neurobiol

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“…However, a recent report on heterozygous deletion of FTase and GGTase‐I showed reduced levels of amyloid beta‐protein and neuroinflammation in a mouse model of AD (Cheng et al . ) which can be interpreted as neuroprotective. The functional roles of prenylated proteins and isoprenoids may differ in normal aging as compared with AD.…”

Section: Discussionmentioning

confidence: 99%

Impaired geranylgeranyltransferase‐I regulation reduces membrane‐associated Rho protein levels in aged mouse brain

Afshordel

Wood

Igbavboa

et al. 2014

Journal of Neurochemistry

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Synaptic impairment rather than neuronal loss may be the leading cause of cognitive dysfunction in brain aging. Certain small Rho-GTPases are involved in synaptic plasticity, and their dysfunction is associated with brain aging and neurodegeneration. Rho-GTPases undergo prenylation by attachment of geranylgeranylpyrophosphate (GGPP) catalyzed by GGTase-I. We examined age-related changes in the abundance of Rho and Rab proteins in membrane and cytosolic fractions as well as of GGTase-I in brain tissue of 3-and 23-month-old C57BL/6 mice. We report a shift in the cellular localization of Rho-GTPases toward reduced levels of membrane-associated and enhanced cytosolic levels of those proteins in aged mouse brain as compared with younger mice.The age-related reduction in membrane-associated Rho proteins was associated with a reduction in GGTase-Ib levels that regulates binding of GGPP to Rho-GTPases. Proteins prenylated by GGTase-II were not reduced in aged brain indicating a specific targeting of GGTase-I in the aged brain. Inhibition of GGTase-I in vitro modeled the effects of aging we observed in vivo. We demonstrate for the first time a decrease in membrane-associated Rho proteins in aged brain in association with down-regulation of GGTase-Ib. This down-regulation could be one of the mechanisms causing age-related weakening of synaptic plasticity.

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“…In support of the hypothesis that SV-mediated inhibition of isoprenoid production and protein prenylation modulates LTP, we have demonstrated previously that supplement of FPP abolishes the enhancement of LTP by SV and that inhibition of farnesyltransferase mimics the effects of SV treatment (Mans et al 2012). Recently, we found that genetic reduction of farne-syltransferase rescues cognitive function in a mouse model of Alzheimer’s disease (Cheng et al 2013). Others have also shown that SV exerts neuroprotective effects by inhibiting activation of small GTPases (Lapchak and Han 2010; Ghosh et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Treatment Enhances NMDAR-Mediated Synaptic Transmission by Upregulating the Surface Distribution of the GluN2B Subunit

et al. 2014

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The ramifications of statins on plasma cholesterol and coronary heart disease have been well documented. However, there is increasing evidence that inhibition of the mevalonate pathway may provide independent neuroprotective and procognitive pleiotropic effects, most likely via inhibition of isoprenoids, mainly farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). FPP and GGPP are the major donors of prenyl groups for protein prenylation. Modulation of isoprenoid availability impacts a slew of cellular processes including synaptic plasticity in the hippocampus. Our previous work has demonstrated that simvastatin (SV) administration improves hippocampusdependent spatial memory, rescuing memory deficits in a mouse model of Alzheimer’s disease. Treatment of hippocampal slices with SV enhances long-term potentiation (LTP), and this effect is dependent on the activation of Akt (protein kinase B). Further studies showed that SV-induced enhancement of hippocampal LTP is driven by depletion of FPP and inhibition of farnesylation. In the present study, we report the functional consequences of exposure to SV at cellular/synaptic and molecular levels. While application of SV has no effect on intrinsic membrane properties of CA1 pyramidal neurons, including hyperpolarization-activated cyclic-nucleotide channel-mediated sag potentials, the afterhyperpolarization (AHP), and excitability, SV application potentiates the N-methyl D-aspartate receptor (NMDAR)-mediated contribution to synaptic transmission. In mouse hippocampal slices and human neuronal cells, SV treatment increases the surface distribution of the GluN2B subunit of the NMDAR without affecting cellular cholesterol content. We conclude that SV-induced enhancement of synaptic plasticity in the hippocampus is likely mediated by augmentation of synaptic NMDAR components that are largely responsible for driving synaptic plasticity in the CA1 region.

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Farnesyltransferase Haplodeficiency Reduces Neuropathology and Rescues Cognitive Function in a Mouse Model of Alzheimer Disease

Cited by 40 publications

References 48 publications

Inhibiting Geranylgeranylation Increases Neurite Branching and Differentially Activates Cofilin in Cell Bodies and Growth Cones

Inhibiting Geranylgeranylation Increases Neurite Branching and Differentially Activates Cofilin in Cell Bodies and Growth Cones

Impaired geranylgeranyltransferase‐I regulation reduces membrane‐associated Rho protein levels in aged mouse brain

Simvastatin Treatment Enhances NMDAR-Mediated Synaptic Transmission by Upregulating the Surface Distribution of the GluN2B Subunit

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