New Treatment for Alzheimer’s Disease, Kamikihito, Reverses Amyloid-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mrow><mml:mi mathvariant="bold-italic">β</mml:mi></mml:mrow></mml:math>-Induced Progression of Tau Phosphorylation and Axonal Atrophy

Watari, Hidetoshi; Shimada, Yutaka; Tohda, Chihiro

doi:10.1155/2014/706487

Cited by 24 publications

(25 citation statements)

References 31 publications

(40 reference statements)

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“…Aβ(25–35), an active fragment of Aβ, had been previously incubated for 4 days at 37°C to form aggregates. Aβ(25–35) treatment is an appropriate in vitro model of AD because we confirmed that aggregated Aβ(25–35) induced axon atrophy as well as tau phosphorylation in previous studies . The cells were treated with KKT solution (10 µg/mL) or vehicle solution.…”

Section: Methodssupporting

confidence: 82%

“…A clinical study performed using patients with AD and vascular dementia showed that KKT treatment significantly improved memory function . Our previous study also showed that KKT treatment reversed Aβ‐induced tau phosphorylation via protein phosphatase 2A (PP2A) . We did not, however, observe robust inactivation of PP2A by Aβ or robust activation of PP2A by KKT in neurons.…”

Section: Introductioncontrasting

confidence: 53%

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Cytosolic aspartate aminotransferase, a direct binding protein of kamikihito, regulates axon growth

Watari

Shimada

Tohda

2015

Traditional & Kampo Medicine

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Aim: Alzheimer's disease (AD) is the most common cause of dementia. The aim of this study was to identify the direct binding proteins of kamikihito (KKT), a traditional Japanese Kampo medicine used as an anti-AD drug. Method: Using the drug affinity responsive target stability (DARTS) method, cytosolic aspartate aminotransferase (cAST) was identified as the direct binding protein of KKT. Primary cultured cortical neurons were treated with amyloid beta (Aβ)(25-35), and cAST expression and activity were evaluated on western blotting and AST activity assay, respectively. To investigate the effects of AST inhibition and cAST knockdown on KKT activity, cortical neurons were treated with O-(carboxymethyl) hydroxylamine hemihydrochloride (OCHH; an AST inhibitor) or transfected with small interfering ribonucleic acid (siRNA) for cAST. The degree of axon atrophy was then evaluated under those conditions. Results: On DARTS analysis a 42 kDa protein underwent decreased proteolysis when KKT was present. Matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF-MS/MS) indicated that the protein was cAST. cAST in Aβ(25-35)-treated neurons had no change in expression level but the activity was reduced. In contrast, treatment with KKT restored cAST activity to control levels. Treatment of cortical neurons with Aβ(25-35) significantly decreased axonal density. KKT treatment restored axonal density, whereas the KKT-induced increase in axonal density was diminished by OCHH treatment or knockdown of cAST. Conclusion: Aβ(25-35)-triggered cAST inactivation may be related to axonal atrophy. KKT upregulates cAST activity, probably via direct binding to cAST, resulting in axonal growth.

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Section: Methodssupporting

confidence: 82%

Section: Introductioncontrasting

confidence: 53%

Cytosolic aspartate aminotransferase, a direct binding protein of kamikihito, regulates axon growth

Watari

Shimada

Tohda

2015

Traditional & Kampo Medicine

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“…Moreover, it has also been used for amnesia in prescriptions. [13][14][15] Recent studies have revealed that the ethanol extract of EZJ and its constituents produce hypnotic effects through the modulation of neurotransmitter systems including serotonergic and γ-aminobutyric acid (GABA)ergic systems. [16][17][18][19][20] Further, numerous brain pathology models have indicated memory-enhancing effects of EZJ.…”

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confidence: 99%

The Seed of <i>Zizyphus jujuba</i> var. <i>spinosa</i> Attenuates Alzheimer’s Disease-Associated Hippocampal Synaptic Deficits through BDNF/TrkB Signaling

Kwon

Jung

Jing

et al. 2017

Biological & Pharmaceutical Bulletin

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Ziziphus jujuba is a plant, which bears fruits and seeds that are used for medicinal purposes in Traditional oriental medicine. The seed of Zizyphus jujuba var. spinosa (EZJ) has been also traditionally used for psychiatric disorders in Chinese and Korean medicines. Recent findings have indicated that EZJ improves memory impairment, a common symptom of various neurological diseases. However, the effects of EZJ on amyloid β (Aβ) toxicity, which is a main cause of Alzheimer's disease (AD), remain to be elucidated. To illuminate the potential anti-AD effect and mechanism in the mouse hippocampal tissue, we examined the effect of standardized EZJ on Aβ-induced synaptic long-term potentiation (LTP) deficit in the hippocampal tissue. EZJ blocked Aβ-induced LTP deficits in a concentration-dependent manner. Moreover, EZJ increased brain-derived neurotrophic factor (BDNF) level in naïve hippocampal slices. The finding that the blockade of BDNF receptor reduced the effect of EZJ suggests that EZJ ameliorates the Aβ-induced LTP deficit through BDNF/topomyosin receptor kinase B (TrkB) signaling. However, transcription or translation inhibitors failed to block the effect of EZJ, suggesting that BDNF synthesis is not required for the action of EZJ on LTP. Finally, we found that EZJ stimulates plasmin activity. In contrast, plasmin inhibitor blocked the effect of EZJ on the Aβ-induced LTP deficit. Our findings indicate that EZJ ameliorates Aβ-induced LTP deficits through BDNF/TrkB signaling. This phenomenon is induced by a regulatory effect of EZJ on the post-translation modification of BDNF.Key words Zizyphus jujuba var. spinosa; amyloid β (Aβ); long-term potentiation; brain-derived neurotrophic factor (BDNF); plasmin Alzheimer's disease (AD) is a typical neurodegenerative disorder showing progressive memory decline. Learning and memory deficits and the loss of higher cognitive function are observed in the early stage of AD. 1) AD is characterized by the amyloid plaques and neurofibrillary tangles accumulation in the brain. Although the specific initiators of AD still remain unknown, mounting evidence suggests that amyloid β (Aβ) plays an important role in the progress of the AD pathology. Extensive research revealed that soluble Aβ oligomers block hippocampal long-term potentiation (LTP), the cellular model of learning and memory.2,3) These indicated that hippocampal LTP could be a target for developing an anti-AD drug.Brain-derived neurotrophic factor (BDNF) is an endogenous neurotrophin family important for the structural and functional plasticity of the brain. 4,5) In AD patients, BDNF level is decreased in the several brain regions even in pre-clinical stages (very earl time) of AD.6,7) Because BDNF is critical for neuronal survival, neuronal function, synaptic plasticity, and cognition, BDNF deficiency may result from AD pathology.8-10) Recent findings have shown that BDNF has protective effects against the toxic effects of Aβ peptides. 11) Therefore, BDNF and its signaling activators are being investigated for applicat...

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“…46) A small scale clinical study was performed using patients with AD and vascular dementia, and showed significant amelioration of memory function. 59) Our study found that KKT treatment reversed Aβ-induced tau phosphorylation via protein phosphatase 2A (PP2A). 60) However, inactivation of PP2A by Aβ and activation of PP2A by KKT in neurons was not robust.…”

Section: Usefulness Of Darts Methods For Iden-tifying Unknown Signalingmentioning

confidence: 69%

New Age Therapy for Alzheimer’s Disease by Neuronal Network Reconstruction

Tohda

2016

Biological & Pharmaceutical Bulletin

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Alzheimer's disease (AD) is a recognized incurable neurodegenerative disorder. Clinically prescribed medicines for AD are expected to bring about only slight symptomatic improvement or a delay of its progression. Another strategy, amyloid β (Aβ) lowing agents, has not been successful at memory improvement. We have hypothesized that an improvement in cognitive function requires the construction of neuronal networks, including neurite regeneration and synapse formation; therefore, we have been exploring candidates for radical anti-AD drugs that can restore Aβ-induced neurite atrophy and memory impairment. Our studies found several promising drug candidates that may improve memory dysfunction in AD model mice. The main activity of these drugs is the restoration of damaged axons. Focusing on candidates based on the recovery of neurite atrophy in vitro certainly leads to positive effects on memory improvement also in vivo. This suggests that neuronal network reconstruction may importantly relate to functional recovery in the brain. When identifying the signaling mechanisms of exogenous compounds like natural medicine-derived constituents, molecules directly activated by the compound are hard to be identified. However, the drug affinity responsive target stability (DARTS) analysis may pave the way to an approach to determine the initial molecule of the signaling pathway. Exploring new drug candidates and clarifying their signaling pathways directly relating to neuronal network reconstruction may provide promising therapeutic strategies with which to overcome AD.

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New Treatment for Alzheimer’s Disease, Kamikihito, Reverses Amyloid-β-Induced Progression of Tau Phosphorylation and Axonal Atrophy

Cited by 24 publications

References 31 publications

Cytosolic aspartate aminotransferase, a direct binding protein of kamikihito, regulates axon growth

Cytosolic aspartate aminotransferase, a direct binding protein of kamikihito, regulates axon growth

The Seed of <i>Zizyphus jujuba</i> var. <i>spinosa</i> Attenuates Alzheimer’s Disease-Associated Hippocampal Synaptic Deficits through BDNF/TrkB Signaling

New Age Therapy for Alzheimer’s Disease by Neuronal Network Reconstruction

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