scholarly journals Transforming Growth Factor β2 Is a Neuronal Death-Inducing Ligand for Amyloid-β Precursor Protein

2005 ◽  
Vol 25 (21) ◽  
pp. 9304-9317 ◽  
Author(s):  
Yuichi Hashimoto ◽  
Tomohiro Chiba ◽  
Marina Yamada ◽  
Mikiro Nawa ◽  
Kohsuke Kanekura ◽  
...  
Keyword(s):  
Growth Factor ◽  
Binding Affinity ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Transforming Growth Factor ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Precursor Protein ◽  
Transforming Growth Factor Β2

ABSTRACT APP, amyloid β precursor protein, is linked to the onset of Alzheimer's disease (AD). We have here found that transforming growth factor β2 (TGFβ2), but not TGFβ1, binds to APP. The binding affinity of TGFβ2 to APP is lower than the binding affinity of TGFβ2 to the TGFβ receptor. On binding to APP, TGFβ2 activates an APP-mediated death pathway via heterotrimeric G protein Go, c-Jun N-terminal kinase, NADPH oxidase, and caspase 3 and/or related caspases. Overall degrees of TGFβ2-induced death are larger in cells expressing a familial AD-related mutant APP than in those expressing wild-type APP. Consequently, superphysiological concentrations of TGFβ2 induce neuronal death in primary cortical neurons, whose one allele of the APP gene is knocked in with the V642I mutation. Combined with the finding indicated by several earlier reports that both neural and glial expression of TGFβ2 was upregulated in AD brains, it is speculated that TGFβ2 may contribute to the development of AD-related neuronal cell death.

scholarly journals Transforming growth factor β2 autocrinally mediates neuronal cell death induced by amyloid-β

2015 ◽  
Vol 93 (6) ◽  
pp. 984-984
Author(s):  
Yuichi Hashimoto ◽  
Mikiro Nawa ◽  
Tomohiro Chiba ◽  
Sadakazu Aiso ◽  
Ikuo Nishimoto ◽  
...  
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Transforming Growth Factor Β2

Transforming growth factor β2 autocrinally mediates neuronal cell death induced by amyloid-β

2006 ◽  
Vol 83 (6) ◽  
pp. 1039-1047 ◽  
Author(s):  
Yuichi Hashimoto ◽  
Mikiro Nawa ◽  
Tomohiro Chiba ◽  
Sadakazu Aiso ◽  
Ikuo Nishimoto ◽  
...  
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Transforming Growth Factor Β2

scholarly journals Overexpression of Mitochondrial Calcium Uniporter Causes Neuronal Death

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Veronica Granatiero ◽  
Marco Pacifici ◽  
Anna Raffaello ◽  
Diego De Stefani ◽  
Rosario Rizzuto
Keyword(s):  
Cell Fate ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Neuronal Loss ◽  
Calcium Uniporter ◽  
Organelle Morphology

Neurodegenerative diseases are a large and heterogeneous group of disorders characterized by selective and progressive death of specific neuronal subtypes. In most of the cases, the pathophysiology is still poorly understood, although a number of hypotheses have been proposed. Among these, dysregulation of Ca2+ homeostasis and mitochondrial dysfunction represent two broadly recognized early events associated with neurodegeneration. However, a direct link between these two hypotheses can be drawn. Mitochondria actively participate to global Ca2+ signaling, and increases of [Ca2+] inside organelle matrix are known to sustain energy production to modulate apoptosis and remodel cytosolic Ca2+ waves. Most importantly, while mitochondrial Ca2+ overload has been proposed as the no-return signal, triggering apoptotic or necrotic neuronal death, until now direct evidences supporting this hypothesis, especially in vivo, are limited. Here, we took advantage of the identification of the mitochondrial Ca2+ uniporter (MCU) and tested whether mitochondrial Ca2+ signaling controls neuronal cell fate. We overexpressed MCU both in vitro, in mouse primary cortical neurons, and in vivo, through stereotaxic injection of MCU-coding adenoviral particles in the brain cortex. We first measured mitochondrial Ca2+ uptake using quantitative genetically encoded Ca2+ probes, and we observed that the overexpression of MCU causes a dramatic increase of mitochondrial Ca2+ uptake both at resting and after membrane depolarization. MCU-mediated mitochondrial Ca2+ overload causes alteration of organelle morphology and dysregulation of global Ca2+ homeostasis. Most importantly, MCU overexpression in vivo is sufficient to trigger gliosis and neuronal loss. Overall, we demonstrated that mitochondrial Ca2+ overload is per se sufficient to cause neuronal cell death both in vitro and in vivo, thus highlighting a potential key step in neurodegeneration.

scholarly journals E2-25K/Hip-2 regulates caspase-12 in ER stress–mediated Aβ neurotoxicity

2008 ◽  
Vol 182 (4) ◽  
pp. 675-684 ◽  
Author(s):  
Sungmin Song ◽  
Huikyong Lee ◽  
Tae-In Kam ◽  
Mei Ling Tai ◽  
Joo-Yong Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Cortical Neurons ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Ubiquitin Proteasome System ◽  
Proteolytic Activation ◽  
Upstream Regulator ◽  
Caspase 12

Amyloid-β (Aβ) neurotoxicity is believed to contribute to the pathogenesis of Alzheimer's disease (AD). Previously we found that E2-25K/Hip-2, an E2 ubiquitin-conjugating enzyme, mediates Aβ neurotoxicity. Here, we report that E2-25K/Hip-2 modulates caspase-12 activity via the ubiquitin/proteasome system. Levels of endoplasmic reticulum (ER)–resident caspase-12 are strongly up-regulated in the brains of AD model mice, where the enzyme colocalizes with E2-25K/Hip-2. Aβ increases expression of E2-25K/Hip-2, which then stabilizes caspase-12 protein by inhibiting proteasome activity. This increase in E2-25K/Hip-2 also induces proteolytic activation of caspase-12 through its ability to induce calpainlike activity. Knockdown of E2-25K/Hip-2 expression suppresses neuronal cell death triggered by ER stress, and thus caspase-12 is required for the E2-25K/Hip-2–mediated cell death. Finally, we find that E2-25K/Hip-2–deficient cortical neurons are resistant to Aβ toxicity and to the induction of ER stress and caspase-12 expression by Aβ. E2-25K/Hip-2 is thus an essential upstream regulator of the expression and activation of caspase-12 in ER stress–mediated Aβ neurotoxicity.

scholarly journals High-Phytate Diets Increase Amyloid β Deposition and Apoptotic Neuronal Cell Death in a Rat Model

Nutrients ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 4370
Author(s):  
Hyo-Jung Kim ◽  
Yun-Shin Jung ◽  
Yun-Jae Jung ◽  
Ok-Hee Kim ◽  
Byung-Chul Oh
Keyword(s):  
Cell Death ◽  
Transcriptional Activation ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Precursor Protein ◽  
Substantial Risk ◽  
Aβ Generation ◽  
Hydrolysis Of ◽  
Immunohistochemical Analyses

Amyloid-β (Aβ) accumulation in the hippocampus is an essential event in the pathogenesis of Alzheimer’s disease. Insoluble Aβ is formed through the sequential proteolytic hydrolysis of the Aβ precursor protein, which is cleaved by proteolytic secretases. However, the pathophysiological mechanisms of Aβ accumulation remain elusive. Here, we report that rats fed high-phytate diets showed Aβ accumulation and increased apoptotic neuronal cell death in the hippocampus through the activation of the amyloidogenic pathway in the hippocampus. Immunoblotting and immunohistochemical analyses confirmed that the overexpression of BACE1 β-secretase, a critical enzyme for Aβ generation, exacerbated the hippocampal Aβ accumulation in rats fed high-phytate diets. Moreover, we identified that parathyroid hormone, a physiological hormone responding to the phytate-mediated dysregulation of calcium and phosphate homeostasis, plays an essential role in the transcriptional activation of the Aβ precursor protein and BACE1 through the vitamin D receptor and retinoid X receptor axis. Thus, our findings suggest that phytate-mediated dysregulation of calcium and phosphate is a substantial risk factor for elevated Aβ accumulation and apoptotic neuronal cell death in rats.

scholarly journals Pro-Nerve Growth Factor Induces Activation of RhoA Kinase and Neuronal Cell Death

2019 ◽  
Vol 9 (8) ◽  
pp. 204 ◽  
Author(s):  
Marina Sycheva ◽  
Jake Sustarich ◽  
Yuxian Zhang ◽  
Vaithinathan Selvaraju ◽  
Thangiah Geetha ◽  
...  
Keyword(s):  
Cell Death ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Kinase Activity ◽  
Kinase Inhibitor ◽  
Neuronal Cell Death ◽  
Rho Kinase ◽  
Neuronal Cell ◽  
Nerve Growth ◽  
Rhoa Kinase

We have previously shown that the expression of pro-nerve growth factor (proNGF) was significantly increased, nerve growth factor (NGF) level was decreased, and the expression of p75NTR was enhanced in Alzheimer’s disease (AD) hippocampal samples. NGF regulates cell survival and differentiation by binding TrkA and p75NTR receptors. ProNGF is the precursor form of NGF, binds to p75NTR, and induces cell apoptosis. The objective of this study is to determine whether the increased p75NTR expression in AD is due to the accumulation of proNGF and Rho kinase activation. PC12 cells were stimulated with either proNGF or NGF. Pull-down assay was carried out to determine the RhoA kinase activity. We found the expression of p75NTR was enhanced by proNGF compared to NGF. The proNGF stimulation also increased the RhoA kinase activity leading to apoptosis. The expression of active RhoA kinase was found to be increased in human AD hippocampus compared to control. The addition of RhoA kinase inhibitor Y27632 not only blocked the RhoA kinase activity but also reduced the expression of p75NTR receptor and inhibited the activation of JNK and MAPK induced by proNGF. This suggests that overexpression of proNGF in AD enhances p75NTR expression and activation of RhoA, leading to neuronal cell death.

scholarly journals Effects of S-2474, a novel nonsteroidal anti-inflammatory drug, on amyloid β protein-induced neuronal cell death

2001 ◽  
Vol 134 (3) ◽  
pp. 673-681 ◽  
Author(s):  
Tatsurou Yagami ◽  
Keiichi Ueda ◽  
Kenji Asakura ◽  
Toshiyuki Sakaeda ◽  
Takayuki Kuroda ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Amyloid Β ◽  
Neuronal Cell ◽  
Amyloid Β Protein ◽  
Inflammatory Drug ◽  
Β Protein ◽  
Anti Inflammatory
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