Intracellular Amyloid &amp;#946;-Protein and Its Associated Molecules in the Pathogenesis of Alzheimers Disease

Ohyagi, Yasumasa; Tabira, Takeshi

doi:10.2174/138955706778560175

Cited by 25 publications

(17 citation statements)

References 59 publications

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“…Further, extracellular addition of Aβ to neuronal cells in culture is known to induce the uptake of Aβ and its localization to the nucleus [42], [43]. In our study, cultures treated with Aβ alone (Fig.2B) showed much more marked internalization of the toxic peptide compared to cultures treated with Aβ plus ASH (Fig.2D).…”

Section: Discussionsupporting

confidence: 51%

β-Amyloid1-42, HIV-1Ba-L (Clade B) Infection and Drugs of Abuse Induced Degeneration in Human Neuronal Cells and Protective Effects of Ashwagandha (Withania somnifera) and Its Constituent Withanolide A

et al. 2014

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Alzheimer's disease (AD) is characterized by progressive dysfunction of memory and higher cognitive functions with abnormal accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles throughout cortical and limbic brain regions. Withania somnifera (WS) also known as ‘ashwagandha’ (ASH) is used widely in Ayurvedic medicine as a nerve tonic and memory enhancer. However, there is paucity of data on potential neuroprotective effects of ASH against β-Amyloid (1–42) (Aβ) induced neuropathogenesis. In the present study, we have tested the neuroprotective effects of Methanol: Chloroform (3:1) extract of ASH and its constituent Withanolide A (WA) against Aβ induced toxicity, HIV-1Ba-L (clade B) infection and the effects of drugs of abuse using a human neuronal SK-N-MC cell line. Aβ when tested individually, induced cytotoxic effects in SK-N-MC cells as shown by increased trypan blue stained cells. However, when ASH was added to Aβ treated cells the toxic effects were neutralized. This observation was supported by cellular localization of Aβ, MTT formazan exocytosis, and the levels of acetylcholinesterase activity, confirming the chemopreventive or protective effects of ASH against Aβ induced toxicity. Further, the levels of MAP2 were significantly increased in cells infected with HIV-1Ba-L (clade B) as well as in cells treated with Cocaine (COC) and Methamphetamine (METH) compared with control cells. In ASH treated cells the MAP2 levels were significantly less compared to controls. Similar results were observed in combination experiments. Also, WA, a purified constituent of ASH, showed same pattern using MTT assay as a parameter. These results suggests that neuroprotective properties of ASH observed in the present study may provide some explanation for the ethnopharmacological uses of ASH in traditional medicine for cognitive and other HIV associated neurodegenerative disorders and further ASH could be a potential novel drug to reduce the brain amyloid burden and/or improve the HIV-1 associated neurocognitive impairments

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Section: Discussionsupporting

confidence: 51%

β-Amyloid1-42, HIV-1Ba-L (Clade B) Infection and Drugs of Abuse Induced Degeneration in Human Neuronal Cells and Protective Effects of Ashwagandha (Withania somnifera) and Its Constituent Withanolide A

et al. 2014

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“…Extracellular Aβ enters the cell under oxidative and heat stress (Ohyagi et al, 2005; Ohyagi and Tabira, 2006; Ohyagi et al, 2007) and is transported to the nucleus by action of the Aβ–related death–inducing protein (AβDIP) (Ohyagi, 2008). Intracellular Aβ induces an increase in levels of the apoptosis–associated tumor protein 53 (p53, gene name TP53) (Ohyagi et al, 2005), the transcription factor achaete–scute complex homolog 1 ( ASCL1 ) (Uchida et al, 2007), and transcription of the β–amyloid cleaving enzyme 1/β–secretase BACE1 gene (Giliberto et al, 2009; Tabaton et al, 2010), while reducing levels of oligodendrocyte lineage transcription factor 2 ( OLIG2 ) (Uchida et al, 2007) and system A glutamine transporter 1 ( SAT1 / SLC38A1 ) (Buntup et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Functional activity of the novel Alzheimer's amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis

Bailey

Maloney

et al. 2011

Gene

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Amyloid β peptide (Aβ) plaque in the brain is the primary (post mortem) diagnostic criterion of Alzheimer’s disease (AD). Any physiological role of Aβ constituent is poorly understood. We have previously determined an Aβ interacting domain (AβID) in the promoters of AD–associated genes (Maloney and Lahiri, 2011). This AβID interacts in a DNA–sequence specific manner with Aβ. We now demonstrate novel Aβ activity as a possible transcription factor. Herein, we demonstrate Aβ–chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma (SK–N–SH) cells treated with FITC conjugated Aβ1–40 localized Aβ to the nucleus in the presence of H2O2–mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter–luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter–CAT fusion clones. Transfected cells were treated with different Aβ peptides and/or H2O2. Aβ treatment of cell cultures produced a DNA sequence–specific response in cells transfected with polymorphic APP clones. Our results suggest the Aβ peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD.

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“…PS-1 mutation causes a selective increase in Aβ42 relative to Aβ40 both in cultured cells and brains of transgenic mice (Borchelt et al 1996;Duff et al 1996; transgenic mice bearing L286V PS-1 mutation exhibited significantly higher intracellular Aβ deposit-positive neurons than control and wild-type transgenic mice and neurodegeneration in AD without formation of extracellular plaques. More and more studies support the early pathogenic role of intracellular deposit of Aβ in the pathogenesis of AD (Ohyagi and Tabira 2006;Gouras et al 2005). Thus, transgenic mice expressing mutant PS-1 could serve as an ideal early AD model to explore the pathophysiology of AD and monitor therapeutic effects of drugs.…”

Section: Introductionmentioning

confidence: 99%

Coenzyme Q10 Attenuates β-Amyloid Pathology in the Aged Transgenic Mice with Alzheimer Presenilin 1 Mutation

Yang

et al. 2008

J Mol Neurosci

100

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One of the neuropathological features of Alzheimer's disease (AD) is the deposition of senile plaques containing beta-amyloid (A beta). There is limited evidence for the treatment to arrest A beta pathology of AD. In our present study, we tested the effect of coenzyme Q10 (CoQ10), an endogenous antioxidant and a powerful free radical scavenger, on A beta in the aged transgenic mice overexpressing Alzheimer presenilin 1-L235P (leucine-to-proline mutation at codon 235, 16-17 months old). The treatment by feeding the transgenic mice with CoQ10 for 60 days (1,200 mg kg(-1) day(-1)) partially attenuated A beta overproduction and intracellular A beta deposit in the cortex of the transgenic mice compared with the age-matched untreated transgenic mice. Meanwhile, an increased oxidative stress reaction was detected as evidenced by elevated level of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) in the transgenic mice relative to the wild-type mice, and supplementation of CoQ10 partially decreased MDA level and upregulated the activity of SOD. The results indicate that oxidative stress is enhanced in the brain of the transgenic mice, that this enhancement may further promote A beta 42 overproduction in a vicious formation, and that CoQ10 would be beneficial for the therapy of AD.

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Intracellular Amyloid β-Protein and Its Associated Molecules in the Pathogenesis of Alzheimers Disease

Cited by 25 publications

References 59 publications

β-Amyloid1-42, HIV-1Ba-L (Clade B) Infection and Drugs of Abuse Induced Degeneration in Human Neuronal Cells and Protective Effects of Ashwagandha (Withania somnifera) and Its Constituent Withanolide A

β-Amyloid1-42, HIV-1Ba-L (Clade B) Infection and Drugs of Abuse Induced Degeneration in Human Neuronal Cells and Protective Effects of Ashwagandha (Withania somnifera) and Its Constituent Withanolide A

Functional activity of the novel Alzheimer's amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis

Coenzyme Q10 Attenuates β-Amyloid Pathology in the Aged Transgenic Mice with Alzheimer Presenilin 1 Mutation

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