scholarly journals BH3-only proteins Puma and Beclin1 regulate autophagic death in neurons in response to Amyloid-β

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Akash Saha ◽  
Suraiya Saleem ◽  
Paidi Ramesh Kumar ◽  
Subhas C. Biswas
Keyword(s):  
Neuronal Death ◽  
Cortical Neurons ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Direct Interaction ◽  
Autophagic Flux ◽  
Neuron Death ◽  
Cytochrome C Release ◽  
Apoptotic Protein ◽  
Simultaneous Activation

AbstractAlzheimer’s disease (AD) is characterized by accumulation of senile amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles causing progressive loss of synapse and neuronal death. Out of the various neuron death modalities, autophagy and apoptosis are reported to be the major death paradigms in AD. However, how these two processes lead to neuronal loss is still inconspicuous. Here we report that under Aβ toxicity, aberrant autophagy is induced with inefficient autophagic flux in neurons. Simultaneous activation of both autophagy and apoptosis are seen in primary cortical neurons as well as in transgenic mice brains. We found that induction of autophagy by rapamycin is detrimental for neurons; whereas downregulation of Beclin1, an important autophagy inducing protein, provides significant protection in Aβ treated neuronal cells by blocking cytochrome-c release from the mitochondria. We further report that downregulation of Puma, a BH3-only pro-apoptotic protein, inhibits the induction of aberrant autophagy and also ameliorates the autophagy flux under the influence of Aβ. Notably, stereotactic administration of shRNAs against Puma and Beclin1 in adult Aβ-infused rat brains inhibits both apoptotic and autophagic pathways. The regulation of both of the death processes is brought about by the direct interaction between Puma and Beclin1 upon Aβ treatment. We conclude that both Beclin1 and Puma play essential roles in the neuronal death caused by the induction of aberrant autophagy in AD and targeting their interaction could be vital to understand the crosstalk of autophagy and apoptosis as well as to develop a potential therapeutic strategy in AD.

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 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 Culling less fit neurons protects against amyloid-β-induced brain damage and cognitive and motor decline

2018 ◽  
Author(s):  
Dina S. Coelho ◽  
Silvia Schwartz ◽  
Marisa M. Merino ◽  
Barbara Hauert ◽  
Barbara Topfel ◽  
...  
Keyword(s):  
Brain Damage ◽  
Neuronal Death ◽  
Common Knowledge ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Long Term Memory ◽  
Brain Circuits ◽  
Key Aspects

SummaryAlzheimer’s disease (AD) is the most common form of dementia, impairing cognitive and motor functions. One of the pathological hallmarks of AD is neuronal loss, which is not reflected in mouse models of AD. Therefore, the role of neuronal death is still uncertain. Here, we used a Drosophila AD model expressing a secreted form of human amyloid-β42 peptide and show that it recapitulates key aspects of AD pathology, including neuronal death and impaired long-term memory. We found that neuronal apoptosis is mediated by cell fitness-driven neuronal culling, which selectively eliminates impaired neurons from brain circuits. We show that removal of less fit neurons delays amyloid-β42-induced brain damage and protects against cognitive and motor decline, suggesting that - contrary to common knowledge - neuronal death may have a beneficial effect in AD.

scholarly journals Nuclear envelope dispersion triggered by deregulated Cdk5 precedes neuronal death

2011 ◽  
Vol 22 (9) ◽  
pp. 1452-1462 ◽  
Author(s):  
Kuei-Hua Chang ◽  
Parminder Singh Multani ◽  
Kai-Hui Sun ◽  
Fabien Vincent ◽  
Yolanda de Pablo ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Death ◽  
Cortical Neurons ◽  
Neuronal Cells ◽  
Amyloid Β ◽  
Nuclear Lamina ◽  
Major Mechanism ◽  
Extensive Cell Death ◽  
Extensive Cell

Nuclear fragmentation is a common feature in many neurodegenerative diseases, including Alzheimer’s disease (AD). In this study, we show that nuclear lamina dispersion is an early and irreversible trigger for cell death initiated by deregulated Cdk5, rather than a consequence of apoptosis. Cyclin-dependent kinase 5 (Cdk5) activity is significantly increased in AD and contributes to all three hallmarks: neurotoxic amyloid-β (Aβ), neurofibrillary tangles (NFT), and extensive cell death. Using Aβ and glutamate as the neurotoxic stimuli, we show that deregulated Cdk5 induces nuclear lamina dispersion by direct phosphorylation of lamin A and lamin B1 in neuronal cells and primary cortical neurons. Phosphorylation-resistant mutants of lamins confer resistance to nuclear dispersion and cell death on neurotoxic stimulation, highlighting this as a major mechanism for neuronal death. Rapid alteration of lamin localization pattern and nuclear membrane change are further supported by in vivo data using an AD mouse model. After p25 induction, the pattern of lamin localization was significantly altered, preceding neuronal death, suggesting that it is an early pathological event in p25-inducible transgenic mice. Importantly, lamin dispersion is coupled with Cdk5 nuclear localization, which is highly neurotoxic. Inhibition of nuclear dispersion rescues neuronal cells from cell death, underscoring the significance of this event to Cdk5-mediated neurotoxicity.

scholarly journals NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Mariana Van Zeller ◽  
Diogo M. Dias ◽  
Ana M. Sebastião ◽  
Cláudia A. Valente
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Nlrp3 Inflammasome ◽  
Neuronal Death ◽  
Inflammatory Responses ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Wide Range

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

Protection of amyloid β protein (25–35)-induced neurotoxicity by methanol extract of Smilacis chinae rhizome in cultured rat cortical neurons

2006 ◽  
Vol 106 (2) ◽  
pp. 230-237 ◽  
Author(s):  
Ju Yeon Ban ◽  
Soon Ock Cho ◽  
Sang Bum Koh ◽  
Kyung-Sik Song ◽  
KiWhan Bae ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Methanol Extract ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Β Protein ◽  
Rat Cortical Neurons

Protective effects of glycycoumarin and procyanidin B1, active components of traditional Japanese medicine yokukansan, on amyloid β oligomer-induced neuronal death

2015 ◽  
Vol 159 ◽  
pp. 122-128 ◽  
Author(s):  
Hitomi Kanno ◽  
Zenji Kawakami ◽  
Masahiro Tabuchi ◽  
Kazushige Mizoguchi ◽  
Yasushi Ikarashi ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Amyloid Β ◽  
Protective Effects ◽  
Active Components ◽  
Traditional Japanese Medicine

Functional outcome after intracerebral haemorrhage – a review of the potential role of antiapoptotic agents

2016 ◽  
Vol 27 (3) ◽  
pp. 317-327 ◽  
Author(s):  
Abubakar Tijjani Salihu ◽  
Sangu Muthuraju ◽  
Zamzuri Idris ◽  
Abdul Rahman Izaini Ghani ◽  
Jafri Malin Abdullah
Keyword(s):  
Functional Outcome ◽  
Intracerebral Haemorrhage ◽  
Neuronal Death ◽  
Potential Role ◽  
Management Strategies ◽  
Experimental Studies ◽  
Neuronal Loss ◽  
Multimodality Treatment ◽  
Mortality And Morbidity

AbstractIntracerebral haemorrhage (ICH) is the second most common form of stroke and is associated with greater mortality and morbidity compared with ischaemic stroke. The current ICH management strategies, which mainly target primary injury mechanisms, have not been shown to improve patient’s functional outcome. Consequently, multimodality treatment approaches that will focus on both primary and secondary pathophysiology have been suggested. During the last decade, a proliferation of experimental studies has demonstrated the role of apoptosis in secondary neuronal loss at the periphery of the clot after ICH. Subsequently, the value of certain antiapoptotic agents in reducing neuronal death and improving functional outcome following ICH was evaluated in animal models. Preliminary evidence from those studies strongly supports the potential role of antiapoptotic agents in reducing neuronal death and improving functional outcome after intracerebral haemorrhage. Expectedly, the ongoing and subsequent clinical trials will substantiate these findings and provide clear information on the most potent and safe antiapoptotic agents, their appropriate dosage, and temporal window of action, thereby making them suitable for the multimodality treatment approach.

3,4-Dihydroxybenzoic acid from Smilacis chinae rhizome protects amyloid β protein (25–35)-induced neurotoxicity in cultured rat cortical neurons

2007 ◽  
Vol 420 (2) ◽  
pp. 184-188 ◽  
Author(s):  
Ju Yeon Ban ◽  
Soon Ock Cho ◽  
So-Young Jeon ◽  
KiHwan Bae ◽  
Kyung-Sik Song ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Dihydroxybenzoic Acid ◽  
Β Protein ◽  
Rat Cortical Neurons

scholarly journals SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Federica Banfi ◽  
Alicia Rubio ◽  
Mattia Zaghi ◽  
Luca Massimino ◽  
Giulia Fagnocchi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Neuronal Death ◽  
Neuronal Loss ◽  
Genotoxic Stress ◽  
Protein Product ◽  
Neural Progenitors ◽  
Cell Identity ◽  
Neurodegenerative Process ◽  
Parp 1 ◽  
Shed Light

AbstractThe investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.

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