Actin interaction and regulation of cyclin-dependent kinase 5/p35 complex activity

Xu, Jianfeng; Tsutsumi, Koji; Tokuraku, Kiyotaka; Estes, Katherine A.; Hisanaga, Shin‐ichi; Ikezu, Tsuneya

doi:10.1111/j.1471-4159.2010.06824.x

Cited by 14 publications

(17 citation statements)

References 51 publications

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“…Primary neural stem cell cultures were prepared from mouse embryonic brain at embryonic day 14 as previously described (29,71). Briefly, cells were cultured as neurospheres for 7 d until spheres reached 100 to 150 μm in diameter.…”

Section: Methodsmentioning

confidence: 99%

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

Kiyota

Ingraham

Jacobsen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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125

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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 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-β peptide (Aβ) 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 Aβ oligomer-sensitive manner. Further, FGF2 enhances Aβ phagocytosis in primary cultured microglia, and reduces Aβ 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.

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Section: Methodsmentioning

confidence: 99%

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

Kiyota

Ingraham

Jacobsen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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125

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“…Seven days after infection, cells were fixed with 4% paraformaldehyde (PFA, Sigma-Aldrich) and immunocytochemistry was conducted as reported (44). Briefly, in order to visualize plasma membrane-localized NEP, fixed cells were not permeabilized prior to incubation with blocking buffer containing 5% BSA and 5% normal donkey serum in PBS for 1 hour at room temperature.…”

Section: Methodsmentioning

confidence: 99%

HIV-1 Reduces Aβ-Degrading Enzymatic Activities in Primary Human Mononuclear Phagocytes

Lan

Kiyota

et al. 2011

The Journal of Immunology

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The advent and wide introduction of antiretroviral therapy (ART) has greatly improved the survival and longevity of HIV-infected patients. Unfortunately, despite ART treatment, these patients are still afflicted with many complications including cognitive dysfunction. There is a growing body of reports indicating accelerated deposition of amyloid plaques, which are composed of amyloid-β peptide (Aβ), in HIV-infected brains. Though how HIV viral infection precipitates Aβ accumulation is poorly understood. It is suggested that viral infection leads to increased production and impaired degradation of Aβ. Mononuclear phagocytes (macrophages and microglia) that are productively infected by HIV in brains play a pivotal role in Aβ degradation through the expression and execution of two endopeptidases: neprilysin (NEP) and insulin-degrading enzyme (IDE). Here we report that NEP has the dominant endopeptidase activity towards Aβ in macrophages. Further, we demonstrate that monomeric Aβ degradation by primary cultured macrophages and microglia was significantly impaired by HIV infection. This was accompanied with great reduction of NEP endopeptidase activity, which might be due to the diminished transport of NEP to cell surface and intracellular accumulation at the endoplasmic reticulum and lysosomes. Therefore, these data suggest that malfunction of NEP in infected macrophages may contribute to acceleration of beta amyloidosis in HIV-inflicted brains and modulation of macrophages may be a potential preventative target of Aβ-related cognitive disorders in HIV-affected patients.

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“…We have previously shown that TTBK1 activates Cdk5 via dissociation of Cdk5 from G-actin and recruitment of p35/ p25 to Cdk5 [7,40]. Other evidence has shown that Cdk5 directly phosphorylates CRMP2 at Ser522, which is the priming step of the phosphorylation of CRMP2 at threonine 514 (T514) by GSK3β and this phosphorylation of CRMP2 at T514 is critical for the induction of neurite retraction [13].…”

Section: Ttbk1 Expression and Aβ Stimulation Induces Crmp2 Phosphorylmentioning

confidence: 99%

Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models

Ikezu

Dixie

Koro

et al. 2020

acta neuropathol commun

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The accumulation of phosphorylated tau protein (pTau) in the entorhinal cortex (EC) is the earliest tau pathology in Alzheimer's disease (AD). Tau tubulin kinase-1 (TTBK1) is a neuron-specific tau kinase and expressed in the EC and hippocampal regions in both human and mouse brains. Here we report that collapsin response mediator protein-2 (CRMP2), a critical mediator of growth cone collapse, is a new downstream target of TTBK1 and is accumulated in the EC region of early stage AD brains. TTBK1 transgenic mice show severe axonal degeneration in the perforant path, which is exacerbated by crossing with Tg2576 mice expressing Swedish familial AD mutant of amyloid precursor protein (APP). TTBK1 mice show accumulation of phosphorylated CRMP2 (pCRMP2), in the EC at 10 months of age, whereas age-matched APP/TTBK1 bigenic mice show pCRMP2 accumulation in both the EC and hippocampal regions. Amyloid-β peptide (Aβ) and TTBK1 suppress the kinetics of microtubule polymerization and TTBK1 reduces the neurite length of primary cultured neurons in Rho kinase-dependent manner in vitro. Silencing of TTBK1 or expression of dominant-negative Rho kinase demonstrates that Aβ induces CRMP2 phosphorylation at threonine 514 in a TTBK1-dependent manner, and TTBK1 enhances Aβ-induced CRMP2 phosphorylation in Rho kinase-dependent manner in vitro. Furthermore, TTBK1 expression induces pCRMP2 complex formation with pTau in vitro, which is enhanced upon Aβ stimulation in vitro. Finally, pCRMP2 forms a complex with pTau in the EC tissue of TTBK1 mice in vivo, which is exacerbated in both the EC and hippocampal tissues in APP/TTBK1 mice. These results suggest that TTBK1 and Aβ induce phosphorylation of CRMP2, which may be causative for the neurite degeneration and somal accumulation of pTau in the EC neurons, indicating critical involvement of TTBK1 and pCRMP2 in the early AD pathology.

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Actin interaction and regulation of cyclin-dependent kinase 5/p35 complex activity

Cited by 14 publications

References 51 publications

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

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

HIV-1 Reduces Aβ-Degrading Enzymatic Activities in Primary Human Mononuclear Phagocytes

Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models

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