Cytotoxic mechanisms by M239V presenilin 2, a little‐analyzed Alzheimer's disease‐causative mutant

Abe, Yoichiro; Hashimoto, Yuichi; Tomita, Yusuke; Terashita, Kenzo; Aiso, Sadakazu; Tajima, Hiroto; Niikura, Takako; Matsuoka, Masao; Nishimoto, Ikuo

doi:10.1002/jnr.20163

Cited by 14 publications

(10 citation statements)

References 57 publications

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“…In fact, A treatment of neuronal cells expressing V642I-APP increases cell mortality in vitro [23]. HN suppresses neuronal cell death caused by these FAD-linked mutants and anti-APP antibody [1,20,21,24,25,28]. More importantly, HN blocks cell death induced by cytotoxic A peptides, A 1-42, A 1-43, and A 25-35, in primary cortical neurons [24,25,77].…”

Section: Action Spectrum Of Hnmentioning

confidence: 99%

“…In addition to V642I-APP, Swedish-type APP mutant (K595N/M596L-APP, NL-APP) and FAD-linked PS mutants, M146L-PS1 and N141I-PS2, induce neuronal cell death in vitro [1,3,19,22,23,28,32,76,83,85]. Besides, anti-APP antibodies that recognize the extracellular region of APP function as a putative ligand of APP and induce apoptosis in wild-type APP-expressing neuronal/non-neuronal line cells and primary neurons ( Moreover, A appears to serve as an APP ligand although more specific APP ligand may exist, since APP was demonstrated as one of A -binding proteins on cell surface [44].…”

Section: Action Spectrum Of Hnmentioning

confidence: 99%

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Neuronal Cell Death in Alzheimers Disease and a Neuroprotective Factor, Humanin

Niikura¹,

Tajima²,

Kita

2006

Self Cite

148

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Brain atrophy caused by neuronal loss is a prominent pathological feature of Alzheimer's disease (AD). Amyloid beta (Abeta), the major component of senile plaques, is considered to play a central role in neuronal cell death. In addition to removal of the toxic Abeta, direct suppression of neuronal loss is an essential part of AD treatment; however, no such neuroprotective therapies have been developed. Excess amount of Abeta evokes multiple cytotoxic mechanisms, involving increase of the intracellular Ca(2+) level, oxidative stress, and receptor-mediated activation of cell-death cascades. Such diversity in cytotoxic mechanisms induced by Abeta clearly indicates a complex nature of the AD-related neuronal cell death. We have identified a 24-residue peptide, Humanin (HN), which suppresses in vitro neuronal cell death caused by all AD-related insults, including Abeta, so far tested. The anti-AD effect of HN has been further confirmed in vivo using mice with Abeta-induced amnesia. Altogether, such potent neuroprotective activity of HN against AD-relevant cytotoxicity both in vitro and in vivo suggests the potential clinical applications of HN in novel AD therapies aimed at controlling neuronal death.

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Section: Action Spectrum Of Hnmentioning

confidence: 99%

Section: Action Spectrum Of Hnmentioning

confidence: 99%

Neuronal Cell Death in Alzheimers Disease and a Neuroprotective Factor, Humanin

Niikura¹,

Tajima²,

Kita

2006

Self Cite

148

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“…There is convincing evidence suggesting a role for glial cell NADPH oxidase in Abeta-induced neurotoxicity (19,(64)(65)(66)(67). Furthermore, the cytotoxic effects of familial AD-causative mutants could be inhibited by apocynin (68,69). However, chronic apocynin treatment failed to improve cognitive deficits in transgenic mouse models of AD, although some positive changes in neuropathology have been shown.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

The neuroprotective effects of apocynin

Simonyi¹

2012

Front Biosci

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The recognition of health benefits of phytomedicines and herbal supplements lead to an increased interest to understand the cellular and molecular basis of their biological activities. Apocynin (4-hydroxy-3-methoxy-acetophenone) is a constituent of the Himalayan medicinal herb Picrorhiza kurroa which is regarded as an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, a superoxide-producing enzyme. NADPH oxidase appears to be especially important in the modulation of redox-sensitive signaling pathways and also has been implicated in neuronal dysfunction and degeneration, and neuroinflammmation in diseases ranging from stroke, Alzheimer's and Parkinson's diseases to psychiatric disorders. In this review, we aim to give an overview of current literature on the neuroprotective effects of apocynin in the prevention and treatment of neurodegenerative disorders. Particular attention is given to in vivo studies. KeywordsApocynin; NADPH oxidase; NOX2; Neurodegeneration; Animal models; Review INTRODUCTIONApocynin (4-hydroxy-3-methoxy-acetophenone) was first isolated from Apocynum species. Two North American species of Apocynum, A. androsaemifolium and A. cannabinum, were widely used by Native American tribes as medicine (1). In addition, Apocynum venetum is used as a tea in north China and Japan and reported to have hepatoprotective effects (2). Apocynin may also be obtained from other plants, e.g. from the rhizome of Iris species.Apocynin was discovered during activity-guided isolation of immunomodulatory constituents from Picrorhiza kurroa, an endangered medicinal plant native to the mountains of India, Nepal, Tibet and Pakistan. Picrorhiza kurroa has been used to treat liver diseases, upper respiratory tract disorders, chronic diarrhea, scorpion sting and fever in the Ayurvedic system of medicine (3). In traditional Chinese medicine, Picrorhiza has been used to treat Send correspondence to: Agnes Simonyi, Department of Biochemistry, 117 Schweitzer Hall, University of Columbia, MO 65211, simonyia@missouri.edu. NIH Public Access Author ManuscriptFront Biosci (Elite Ed It is important to note that no adverse side effects of Picrorhiza extract/apocynin have been reported (3). Apocynin has a very good safety profile in animal studies as well (4), and several studies used long-term treatment without any signs of ill-health effects (see the studies with transgenic mice of Alzheimer's disease, for an example). Our recent study on the bioavailability of apocynin showed that apocynin is rapidly metabolized into glucuronic conjugate (5). At 30 min and 1 h after injection (5 mg/kg body wt, i.p.), approximately 50% of apocynin was converted to its glycosyl derivative and was distributed in plasma, liver and brain. Apocynin appeared in plasma as early as 30 min, peaked at 1 h and declined to low levels after 2 h (5). Following intragastric administration, apocynin is shown to undergo rapid absorption and excretion; with urinary excretion containing the unchanged form, the glucuronide, demethylat...

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“…AD is associated with the accumulation of the amyloid precursor protein (APP) cleavage product Aβ 42 , which forms the amyloid plaques characteristic of the disease. In F11 cells, a cell line created from the fusion of mouse neuroblastoma N18TG-2 cells with embryonic rat dorsal root ganglion neurons, EcD-induced expression of transfected mutant presenilin-2 (M239V presenilin-2), the γ-secretase implicated in cleavage of APP to Aβ 42 , induces apoptosis through Gα o [90]. These effects were abrogated by inhibition of Caspase-3 and by pertussis toxin.…”

Section: Review Of Literature On G Protein Regulation Of Apoptosismentioning

confidence: 99%

Heterotrimeric G Proteins and Apoptosis: Intersecting Signaling Pathways Leading to Context Dependent Phenotypes

Yanamadala¹,

Negoro²,

Denker³

2009

CMM

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Apoptosis, a programmed cell death mechanism, is a fundamental process during the normal development and somatic maintenance of all multicellular organisms and thus is highly conserved and tightly regulated through numerous signaling pathways. Apoptosis is of particular clinical importance as its dysregulation contributes significantly to numerous human diseases, primarily through changes in the expression and activation of key apoptotic regulators. Each of the four families of heterotrimeric G proteins (Gs, Gi/o, Gq/11 and G12/13) has been implicated in numerous cellular signaling processes, including proliferation, transformation, migration, differentiation, and apoptosis. Heterotrimeric G protein signaling is an important but not widely studied mechanism regulating apoptosis. G protein Signaling and Apoptosis broadly cover two large bodies of literature and share numerous signaling pathways. Examination of the intersection between these two areas is the focus of this review. Several studies have implicated signaling through each of the four heterotrimeric G protein families to regulate apoptosis within numerous disease contexts, but the mechanism(s) are not well defined. Each G protein family has been shown to stimulate and/or inhibit apoptosis in a context-dependent fashion through regulating numerous downstream effectors including the Bcl-2 family, NF-κB, PI3 Kinase, MAP Kinases, and small GTPases. These cell-type specific and G protein coupled receptor dependent effects have led to a complex body of literature of G protein regulation of apoptosis. Here, we review the literature and summarize apoptotic signaling through each of the four heterotrimeric G protein families (and the relevant G protein coupled receptors), and discuss limitations and future directions for research on regulating apoptosis through G protein coupled mechanisms. Continued investigation in this field is essential for the identification of important targets for pharmacological intervention in numerous diseases.

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Cytotoxic mechanisms by M239V presenilin 2, a little‐analyzed Alzheimer's disease‐causative mutant

Cited by 14 publications

References 57 publications

Neuronal Cell Death in Alzheimers Disease and a Neuroprotective Factor, Humanin

Neuronal Cell Death in Alzheimers Disease and a Neuroprotective Factor, Humanin

The neuroprotective effects of apocynin

Heterotrimeric G Proteins and Apoptosis: Intersecting Signaling Pathways Leading to Context Dependent Phenotypes

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