Rapid Tau Aggregation and Delayed Hippocampal Neuronal Death Induced by Persistent Thrombin Signaling

Suo, Zhiming; Wu, Mingqin; Citron, Bruce A.; Palazzo, Robert E.; Festoff, Barry W.

doi:10.1074/jbc.m301406200

Cited by 87 publications

(72 citation statements)

References 104 publications

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“…Selected lines of HT22/dnGRK5GFP/M2, HT22/wtGRK5GFP/ M2, and HT22/GFP/M2 that express equivalent numbers of the transgene copies were used for this study. For all functional assays, the HT22 cells were differentiated, as previously described (19), before any treatments were applied.…”

Section: Materials-[methyl-mentioning

confidence: 99%

“…HT22 cells seeded at a density of 5 ϫ 10 5 cells/well in six-well plates were allowed for differentiation, as previously described (19). The cells were then incubated with medium containing [methyl- (20).…”

Section: Materials-[methyl-mentioning

confidence: 99%

“…For the mice, at euthanasia, cold phosphate-buffered saline-perfused brains were dissected to obtain hippocampus. Except for the cellular fraction preparation, which is described above, all other protein extract preparation, total protein content determination, Western blotting, and semi-quantitative analyses were performed as previously described (5,19,25). The only exception was the dilution rates for the different primary antibodies, which include synaptophysin (Sigma; 1:400), synapsin-IIa (BD Biosciences, San Jose, CA; 1:5,000), synaptotagmin (BD Biosciences; 1:1,000), SNAP-25 (BD Biosciences; 1:1,000), neuronal growth associated protein-43 (GAP-43; Sigma; 1:500), M1 and M4 (Santa Cruz Biotechnology, Santa Cruz, CA; 1:200), M2 (Santa Cruz Biotechnology; 1:100), acetylcholine esterase (Santa Cruz Biotechnology; 1:500), choline acetyltransferase (ChAT; Chemicon, Temecula, CA; 1:800), HACT (Chemicon; 1:4,000), vesicular acetylcholine transporter (VAChT; Santa Cruz Biotechnology; 1:200), hrGFP (Stratagene, La Jolla, CA; 1:5,000), and ␤-actin (Sigma; 1:2,500).…”

Section: Materials-[methyl-mentioning

confidence: 99%

“…The cells were cultured in Dulbecco's modified Eagles's medium supplied with 10% fetal bovine serum, 100 g/ml streptomycin, and 100 units/ml penicillin, as previously described (19). Transfection was performed using 0.125-0.25 g of plasmid DNA (pVITRO1-dnGRK5GFP/M2, pVITRO1-wtGRK5GFP/M2, and pVITRO1-GFP/M2) mixed with TransFast TM reagents (Promega), according to the manufacturer's instruction.…”

Section: Materials-[methyl-mentioning

confidence: 99%

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GRK5 Deficiency Leads to Reduced Hippocampal Acetylcholine Level via Impaired Presynaptic M2/M4 Autoreceptor Desensitization

Rasul

Sun

et al. 2009

Journal of Biological Chemistry

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G protein-coupled receptor kinase 5 (GRK5) deficiency has been linked recently to early Alzheimer disease (AD), but the mechanism by which GRK5 deficiency may contribute to AD pathogenesis remains elusive. Here we report that overexpression of dominant negative mutant of GRK5 (dnGRK5) in a cholinergic neuronal cell line led to decreased acetylcholine (ACh) release. This reduction was fully corrected by pertussis toxin, atropine (a nonselective muscarinic antagonist), or methoctramine (a selective M2/M4 muscarinic receptor antagonist). Consistent with results in cultured cells, high potassium-evoked ACh release in hippocampal slices from young GRK5 knock-out mice was significantly reduced compared with wild type littermates, and this reduced ACh release was also fully corrected by methoctramine. In addition, following treatment with the nonselective muscarinic agonist oxotremorine-M, M2, and M4 receptors underwent significantly reduced internalization in GRK5KO slices compared with wild type slices, as assessed by plasma membrane retention of receptor immunoreactivity, whereas M1 receptor internalization was not affected by loss of GRK5 expression. Moreover, Western blotting revealed no synaptic or cholinergic degenerative changes in young GRK5 knock-out mice. Altogether, these results suggest that GRK5 deficiency leads to a reduced hippocampal ACh release and cholinergic hypofunction by selective impairment of desensitization of presynaptic M2/M4 autoreceptors. Because this nonstructural cholinergic hypofunction precedes the hippocampal cholinergic hypofunction associated with structural cholinergic degeneration and cognitive decline in aged GRK5 knock-out mice, this nonstructural alteration may be an early event contributing to cholinergic degeneration in AD.G protein-coupled receptor kinase-5 (GRK5) 2 is one of the seven GRK family members whose primary function is to desensitize G protein-coupled receptors (GPCRs) (1, 2). We recently reported that increased soluble ␤-amyloid decreases membrane (functional) levels of GRK5 in vitro, and this membrane GRK5 deficiency occurs in vivo as well in an Alzheimer disease (AD) transgenic model (3) and in postmortem human AD brain samples (4). Moreover, the aged GRK5 knock-out (GRK5KO) mouse, which models this GRK5 deficiency in the absence of exogenous mutant human ␤-amyloid precursor protein (␤-APP) or any other known AD-related genes (i.e. presenilins or tau), develops axonal defects and mild cholinergic degeneration with associated amnestic mild cognitive impairment (5). When Swedish mutant ␤APP is overexpressed in the GRK5KO mice by cross-breeding with Swedish APP transgenic mice, the aged double mutant mice display significantly exaggerated brain inflammation (6). These accumulating data strongly suggest that GRK5 deficiency significantly contributes to AD pathogenesis, although the precise molecular mechanisms remain to be delineated.Mounting evidence indicates that the substrate spectrum of broadly expressed GRKs (i.e. GRK2/3/5/6) can significantly overlap for som...

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Section: Materials-[methyl-mentioning

confidence: 99%

Section: Materials-[methyl-mentioning

confidence: 99%

Section: Materials-[methyl-mentioning

confidence: 99%

Section: Materials-[methyl-mentioning

confidence: 99%

See 2 more Smart Citations

GRK5 Deficiency Leads to Reduced Hippocampal Acetylcholine Level via Impaired Presynaptic M2/M4 Autoreceptor Desensitization

Rasul

Sun

et al. 2009

Journal of Biological Chemistry

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“…Through a variety of signal transduction mechanisms, PAR-1 has been shown to mediate effects of thrombin on astrocytic proliferation, process retraction, growth factor production, and also neuronal morphology and survival (11,12). PAR-1 has also been implicated in the pathogenesis of neuroinflammatory/degenerative disorders (13,14). Previous studies from our group demonstrated an important role for astrocytic PAR-1 up-regulation and activation in the neuropathogenesis of HIV-1 infection (15), characterized by neuroinflammation and neuronal injury.…”

mentioning

confidence: 99%

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Noorbakhsh

Vergnolle

McArthur

et al. 2005

The Journal of Immunology

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Proteinase-activated receptors (PARs), a newly discovered subgroup of G-protein coupled receptors, are widely expressed by neural cells, but their roles in the nervous system remain uncertain. In this study, we report that PAR-2 was up-regulated on neurons in conjunction with neuroinflammation in brain tissue from patients with HIV-1-associated dementia. The inflammatory cytokines TNF-α and IL-1β were also increased in HIV-1-associated dementia brains compared with patients without dementia (p < 0.05), but these same cytokines induced PAR-2 expression on neurons. Enhanced PAR-2 expression and subsequent activation prevented neuronal cell death and induction of the tumor suppressor, p53, caused by the HIV-encoded protein, Tat (p < 0.01). Intrastriatal implantation of a PAR-2 peptide agonist also inhibited Tat-induced neurotoxicity in a mouse model of HIV neuropathogenesis (p < 0.05). Moreover, PAR-2 null animals showed more severe neuroinflammation and neuronal loss caused by Tat neurotoxicity (p < 0.05). TNF-α protected wild-type neurons from Tat-related neurotoxicity, but in PAR-2-deficient neurons, the same concentrations of TNF-α were cytotoxic (p < 0.001). Thus, neuroinflammation can exert protective effects by which it induces PAR-2 expression with the ensuing abrogation of neuronal death.

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Differential methylation of the micro‐RNA 7b gene targets postnatal maturation of murine neuronal Mecp2 gene expression

Chen

Shin

Thamotharan

et al. 2013

Developmental Neurobiology

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DNA methylation and microRNAs (miRNAs) play crucial roles in maturation of postnatal mouse neurons. Aberrant DNA methylation and/or altered miRNA expression cause postnatal neurodevelopmental disorders. In general, DNA methylation in the 5'-flanking region suppresses gene expression through recruitment of methyl-CpG binding domain proteins (MBPs) to the cytosine residues of CpG dinucleotides. X-linked MeCP2 (methyl-CpG binding protein 2), a member of MBPs, is a methylation-associated transcriptional repressor with other functions in the central nervous system (CNS). miRNAs negatively regulate gene expression by targeting the 3'-untranslated region (3'UTR). Some miRNA genes harboring or being embedded in CpG islands undergo methylation-mediated silencing. One such miRNA is miR-7b which is differentially expressed through stages of neurodevelopment. In our present study, we focused on a canonical CpG island located in the 5'-flanking region of the murine miR-7b gene. Hypermethylation of this CpG island down-regulates miR-7b while recruiting MeCP2 to the methylated CpG dinucleotides. Meanwhile, Mecp2, a target of miR-7b, was up-regulated due to lack of restrain exerted by miR-7b during maturation of postnatal (PN) mouse neurons between PN3 and PN14. Our results indicate that miR-7b is a direct downstream gene transcriptional target while also being a negative post-transcriptional regulator of Mecp2 expression. We speculate that this bidirectional feed-back autoregulatory function of miR-7b and Mecp2 while linking DNA methylation and miRNA action maintains the homeostatic control of gene expression necessary during postnatal maturation of mammalian neurons.

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Rapid Tau Aggregation and Delayed Hippocampal Neuronal Death Induced by Persistent Thrombin Signaling

Cited by 87 publications

References 104 publications

GRK5 Deficiency Leads to Reduced Hippocampal Acetylcholine Level via Impaired Presynaptic M2/M4 Autoreceptor Desensitization

GRK5 Deficiency Leads to Reduced Hippocampal Acetylcholine Level via Impaired Presynaptic M2/M4 Autoreceptor Desensitization

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Differential methylation of the micro‐RNA 7b gene targets postnatal maturation of murine neuronal Mecp2 gene expression

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