Astrocytic Expression of the Immunoreceptor CD300f Protects Hippocampal Neurons from Amyloid-β Oligomer Toxicity In Vitro

Background Alzheimer’s disease (AD) is the primary cause of dementia in the elderly. The imbalance between production and clearance of amyloid β (Aβ) is a very early, often initiating factor in AD. Dendrobium nobile Lindl. alkaloids (DNLA) extracted from a Chinese medicinal herb, which have been shown to have anti-aging effects, protected against neuronal impairment in vivo and in vitro. Moreover, we confirmed that DNLA can improve learning and memory function in elderly normal mice, indicating that DNLA has potential health benefits. However, the underlying mechanism is unclear. Therefore, we further explored the effect of DNLA on neurons, which is closely related to learning and memory, based on Aβ. Methods We exposed cultured hippocampal neurons to DNLA to investigate the effect of DNLA on Aβ in vitro. Cell viability was evaluated by MTT assays. Proteins were analyzed by Western blot analysis. Results The cell viability of hippocampal neurons was not changed significantly after treatment with DNLA. But DNLA reduced the protein expression of amyloid precursor protein (APP), disintegrin and metalloprotease 10 (ADAM10), β-site APP cleaving enzyme 1 (BACE1) and Aβ1–42 of hippocampal neurons in rats and increased the protein expression of ADAM17. Conclusions DNLA decreases Aβ by regulating α- and β-secretase in hippocampal neurons of SD rats.

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Amyloid β peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from Aβ-mediated toxicity in vitro

Biological Chemistry ◽

10.1515/hsz-2013-0230 ◽

2014 ◽

Vol 395 (1) ◽

pp. 109-118 ◽

Cited By ~ 12

Author(s):

Tyler D. Shropshire ◽

Jack Reifert ◽

Sridharan Rajagopalan ◽

David Baker ◽

Stuart C. Feinstein ◽

...

Keyword(s):

Hippocampal Neurons ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Hydrophobic Core ◽

Insulin Degrading Enzyme ◽

Core Motif ◽

Peptide Cleavage ◽

Bacterial Display ◽

Clearance Mechanism

Abstract The gradual accumulation and assembly of β-amyloid (Aβ) peptide into neuritic plaques is a major pathological hallmark of Alzheimer disease (AD). Proteolytic degradation of Aβ is an important clearance mechanism under normal circumstances, and it has been found to be compromised in those with AD. Here, the extended substrate specificity and Aβ-degrading capacity of kallikrein 7 (KLK7), a serine protease with a unique chymotrypsin-like specificity, was characterized. Preferred peptide substrates of KLK7 identified using a bacterial display substrate library were found to exhibit a consensus motif of RXΦ(Y/F)↓(Y/F)↓(S/A/G/T) or RXΦ(Y/F)↓(S/T/A) (Φ=hydrophobic), which is remarkably similar to the hydrophobic core motif of Aβ (K16L17V18F19F20 A21) that is largely responsible for aggregation propensity. KLK7 was found to cleave after both Phe residues within the core of Aβ42 in vitro, thereby inhibiting Aβ fibril formation and promoting the degradation of preformed fibrils. Finally, the treatment of Aβ oligomer preparations with KLK7, but not inactive pro-KLK7, significantly reduced Aβ42-mediated toxicity to rat hippocampal neurons to the same extent as the known Aβ-degrading protease insulin-degrading enzyme (IDE). Taken together, these results indicate that KLK7 possesses an Aβ-degrading capacity that can ameliorate the toxic effects of the aggregated peptide in vitro.

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Tauroursodeoxycholic acid suppresses amyloid β-induced synaptic toxicity in vitro and in APP/PS1 mice

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2012.04.018 ◽

2013 ◽

Vol 34 (2) ◽

pp. 551-561 ◽

Cited By ~ 23

Author(s):

Rita M. Ramalho ◽

Ana F. Nunes ◽

Raquel B. Dias ◽

Joana D. Amaral ◽

Adrian C. Lo ◽

...

Keyword(s):

Amyloid Β ◽

Tauroursodeoxycholic Acid ◽

Toxicity In Vitro

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Poly-N-methylated Amyloid β-Peptide (Aβ) C-Terminal Fragments Reduce Aβ Toxicity in Vitro and inDrosophila melanogaster

Journal of Medicinal Chemistry ◽

10.1021/jm901092h ◽

2009 ◽

Vol 52 (24) ◽

pp. 8002-8009 ◽

Cited By ~ 48

Author(s):

Partha Pratim Bose ◽

Urmimala Chatterjee ◽

Charlotte Nerelius ◽

Thavendran Govender ◽

Thomas Norström ◽

...

Keyword(s):

Amyloid Β ◽

Amyloid Β Peptide ◽

Toxicity In Vitro

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Remodeling of Intracellular Ca2+ Homeostasis in Rat Hippocampal Neurons Aged In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21041549 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1549 ◽

Cited By ~ 5

Author(s):

Maria Calvo-Rodriguez ◽

Elena Hernando-Pérez ◽

Sara López-Vázquez ◽

Javier Núñez ◽

Carlos Villalobos ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Neurodegenerative Disorders ◽

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Neuronal Damage ◽

Amyloid Β ◽

Memory Storage ◽

Amyloid Β Peptide

Aging is often associated with a cognitive decline and a susceptibility to neuronal damage. It is also the most important risk factor for neurodegenerative disorders, particularly Alzheimer’s disease (AD). AD is related to an excess of neurotoxic oligomers of amyloid β peptide (Aβo); however, the molecular mechanisms are still highly controversial. Intracellular Ca2+ homeostasis plays an important role in the control of neuronal activity, including neurotransmitter release, synaptic plasticity, and memory storage, as well as neuron cell death. Recent evidence indicates that long-term cultures of rat hippocampal neurons, resembling aged neurons, undergo cell death after treatment with Aβo, whereas short-term cultures, resembling young neurons, do not. These in vitro changes are associated with the remodeling of intracellular Ca2+ homeostasis with aging, thus providing a simplistic model for investigating Ca2+ remodeling in aging. In vitro aged neurons show increased resting cytosolic Ca2+ concentration, enhanced Ca2+ store content, and Ca2+ release from the endoplasmic reticulum (ER). Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria is also enhanced. Aged neurons also show decreased store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway related to memory storage. At the molecular level, in vitro remodeling is associated with changes in the expression of Ca2+ channels resembling in vivo aging, including changes in N-methyl-D-aspartate NMDA receptor and inositol 1,4,5-trisphosphate (IP3) receptor isoforms, increased expression of the mitochondrial calcium uniporter (MCU), and decreased expression of Orai1/Stim1, the molecular players involved in SOCE. Additionally, Aβo treatment exacerbates most of the changes observed in aged neurons and enhances susceptibility to cell death. Conversely, the solely effect of Aβo in young neurons is to increase ER–mitochondria colocalization and enhance Ca2+ transfer from ER to mitochondria without inducing neuronal damage. We propose that cultured rat hippocampal neurons may be a useful model to investigate Ca2+ remodeling in aging and in age-related neurodegenerative disorders.

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Endogenous Galanin Protects Mouse Hippocampal Neurons Against Amyloid Toxicity in vitro via Activation of Galanin Receptor-2

Journal of Alzheimer s Disease ◽

10.3233/jad-2011-110011 ◽

2011 ◽

Vol 25 (3) ◽

pp. 455-462 ◽

Cited By ~ 24

Author(s):

Caroline R. Elliott-Hunt ◽

Fiona E. Holmes ◽

Dean M. Hartley ◽

Sylvia Perez ◽

Elliott J. Mufson ◽

...

Keyword(s):

Hippocampal Neurons ◽

Galanin Receptor ◽

Amyloid Toxicity ◽

Toxicity In Vitro

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Protein Kinase C Involvement in Neuroprotective Effects of Thymol and Carvacrol Against Toxicity Induced by Amyloid-Β in Rat Hippocampal Neurons

Basic and Clinical Neuroscience Journal ◽

10.32598/bcn.2021.666.2 ◽

2021 ◽

Author(s):

Zahra Azizi ◽

◽

Samira Choopani ◽

Mona Salimi ◽

Nahid Majlessi ◽

...

Keyword(s):

Rat Model ◽

Cognitive Abilities ◽

Hippocampal Neurons ◽

Amyloid Β ◽

Underlying Mechanism ◽

Control Group ◽

Protective Effects ◽

Neuroprotective Effects ◽

Expression Ratio

Introduction: We have reported that thymol and carvacrol can improve cognitive abilities in Alzheimer’s disease (AD) rat model. However, the mechanism of their action is not yet fully understood. Recently, our in vitro results suggested that PC12 cell death-induced by Aβ25-35 can be protected by thymol and carvacrol via PKC and ROS pathways. So, we hypothesize that the mechanisms of thymol and carvacrol in improving the learning impairment in AD rat model may be related to their effects on PKC. So, the activity of PKC and protein expression levels of PKCα was examined in the hippocampal cells of AD rat model. Methods: To examine thymol and carvacrol effects, we performed behavioral test in AD rat model induced by Aβ25–35 neurotoxicity. To access the underlying mechanism of protective effects, western blotting was performed with antibodies against PKCα. We also measured PKC activity assay by Elisa. Histopathological studies were carried out in hippocampus by hematoxylin & eosin (H&E). Results: It was shown that escape latency increased in Aβ-received rats compared to control group and thymol and carvacrol reversed this deficit. Furthermore, these compouds could enhance PKC activity, and increase the PKCα expression ratio. Moreover, H&E showed that Aβ caused shrinkage of the CA1 pyramidal neurons. However, thymol and carvacrol treatments could prevent this effect of Aβ peptides. Conclusions: This study suggests that Aβ results in memory decline and histochemical disturbances in hippocampus. Moreover, these results revealed that thymol and carvacrol could have protective effects on cognition in AD-like models via PKC activation.

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Neurotoxic Ca2+ Signaling Induced by Amyloid–β Oligomers in Aged Hippocampal Neurons In Vitro

Methods in Molecular Biology - Amyloid Proteins ◽

10.1007/978-1-4939-7816-8_20 ◽

2018 ◽

pp. 341-354 ◽

Cited By ~ 2

Author(s):

Lucía Núñez ◽

María Calvo-Rodríguez ◽

Erica Caballero ◽

Mónica García-Durillo ◽

Carlos Villalobos

Keyword(s):

Hippocampal Neurons ◽

Amyloid Β

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Extracellular GAPDH promotes Alzheimer disease progression by enhancing amyloid-β aggregation and cytotoxicity

10.21203/rs.3.rs-53359/v1 ◽

2020 ◽

Author(s):

Vladimir F. Lazarev ◽

Magda Tsolaki ◽

Elena R. Mikhaylova ◽

Konstantin A. Benken ◽

Maxim A. Shevtsov ◽

...

Keyword(s):

Alzheimer Disease ◽

Brain Tissue ◽

Hippocampal Neurons ◽

Neuronal Degeneration ◽

Amyloid Β ◽

Neuronal Cell ◽

Covalent Bond ◽

Terminal Deoxynucleotidyl Transferase ◽

Cellular Models

Abstract Background Neuronal cell death during Alzheimer disease (AD) causes the release of cytosolic proteins, particularly glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which forms highly cytotoxic detergent-insoluble complexes with amyloid-β (Aβ) and promotes neurodegeneration. Methods We detected and quantified the complex formation between Aβ and GAPDH released from brain tissue of patients with AD using ultrafiltration, and fluorescence resonance energy transfer (FRET). To explore the biochemical and structural features of Aβ-GAPDH complexes we employed novel immunoenzyme assays and atomic force microscopy. Lentiviral infection in situ was used to elevate GAPDH in brain tissue of rat and mouse models of AD. The Morris maize water test, MRI, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and lactate dehydrogenase (LDH)-activity assays were used to characterize the effects of Aβ-GAPDH complexes in animal and cellular models of AD. Results Here we report that GAPDH forms stable aggregates with extracellular Aβ. We detected these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD. We found that GAPDH forms a covalent bond with Q15 of Aβ that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between Aβ and GAPDH and reduces Aβ-GAPDH cytotoxicity. Lentivirus-driven GAPDH overexpression in two AD animal models increased the level of apoptosis of hippocampal neurons, neuronal degeneration, and cognitive dysfunction. In contrast, in vivo knockdown of GAPDH reversed these pathogenic abnormalities suggesting a pivotal role of GAPDH in Aβ-stimulated neurodegeneration. CSF obtained from animals with enhanced GAPDH expression demonstrated increased cytotoxicity in vitro . Furthermore, RX-624, a specific GAPDH small molecular ligand reduced accumulation of Aβ aggregates and reversed memory deficit in AD transgenic mice. Conclusions Extracellular GAPDH compromises Aβ clearance and accelerates neurodegeneration, thus representing a promising pharmacological target for AD.

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