Enhancing calmodulin binding to ryanodine receptor is crucial to limit neuronal cell loss in Alzheimer disease

AbstractAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive neuronal cell loss. Recently, dysregulation of intracellular Ca2+ homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Here, we investigated (1) the pathogenic role of destabilization of ryanodine receptor (RyR2) in endoplasmic reticulum (ER) upon development of AD phenotypes in AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic), and (2) the therapeutic effect of enhanced calmodulin (CaM) binding to RyR2. In the neuronal cells from AppNL-G-F mice, CaM dissociation from RyR2 was associated with AD-related phenotypes, i.e. Aβ accumulation, TAU phosphorylation, ER stress, neuronal cell loss, and cognitive dysfunction. Surprisingly, either genetic (by V3599K substitution in RyR2) or pharmacological (by dantrolene) enhancement of CaM binding to RyR2 reversed almost completely the aforementioned AD-related phenotypes, except for Aβ accumulation. Thus, destabilization of RyR2 due to CaM dissociation is most likely an early and fundamental pathogenic mechanism involved in the development of AD. The discovery that neuronal cell loss can be fully prevented simply by stabilizing RyR2 sheds new light on the treatment of AD.

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Transiently lowering tumor necrosis factor-α synthesis ameliorates neuronal cell loss and cognitive impairments induced by minimal traumatic brain injury in mice

Journal of Neuroinflammation ◽

10.1186/s12974-015-0237-4 ◽

2015 ◽

Vol 12 (1) ◽

pp. 45 ◽

Cited By ~ 76

Author(s):

Renana Baratz ◽

David Tweedie ◽

Jia-Yi Wang ◽

Vardit Rubovitch ◽

Weiming Luo ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Cognitive Impairments ◽

Neuronal Cell ◽

Cell Loss ◽

Neuronal Cell Loss ◽

Factor Α ◽

Necrosis Factor

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Neuronal Cell Loss in the CA3 Subfield of the Hippocampus Following Cortical Contusion Utilizing the Optical Disector Method for Cell Counting

Journal of Neurotrauma ◽

10.1089/neu.1997.14.385 ◽

1997 ◽

Vol 14 (6) ◽

pp. 385-398 ◽

Cited By ~ 103

Author(s):

STANLEY A. BALDWIN ◽

TONYA GIBSON ◽

C. TODD CALLIHAN ◽

PATRICK G. SULLIVAN ◽

ERICK PALMER ◽

...

Keyword(s):

Neuronal Cell ◽

Cell Loss ◽

Cell Counting ◽

Optical Disector ◽

Neuronal Cell Loss ◽

Cortical Contusion

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Extent of mossy fiber sprouting in patients with mesiotemporal lobe epilepsy correlates with neuronal cell loss and granule cell dispersion

Epilepsy Research ◽

10.1016/j.eplepsyres.2016.11.011 ◽

2017 ◽

Vol 129 ◽

pp. 51-58 ◽

Cited By ~ 13

Author(s):

Barbara Schmeiser ◽

Josef Zentner ◽

Marco Prinz ◽

Armin Brandt ◽

Thomas M. Freiman

Keyword(s):

Granule Cell ◽

Mossy Fiber ◽

Neuronal Cell ◽

Cell Loss ◽

Mossy Fiber Sprouting ◽

Cell Dispersion ◽

Neuronal Cell Loss

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Estrogens influence on neuronal cell loss in the MPTP model for Parkinson disease

Neuro-Visionen 4 ◽

10.30965/9783657764082_064 ◽

2007 ◽

pp. 143-144

Keyword(s):

Parkinson Disease ◽

Neuronal Cell ◽

Cell Loss ◽

Neuronal Cell Loss ◽

Mptp Model

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Non-Alzheimer Dementia with Status spongiosus and Neuronal Cell Loss Showing Unusual Perineuronal Structures and Point Mutation at 129 Codon of Prion Protein

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000106601 ◽

1996 ◽

Vol 8 (1) ◽

pp. 55-59

Author(s):

M. Hayashi ◽

K. Kobayashi ◽

C. Ishida ◽

T. Aoki ◽

F. Muramori ◽

...

Keyword(s):

Point Mutation ◽

Prion Protein ◽

Neuronal Cell ◽

Cell Loss ◽

Status Spongiosus ◽

Alzheimer Dementia ◽

Neuronal Cell Loss

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NADPH Oxidase Mediates Membrane Androgen Receptor–Induced Neurodegeneration

Endocrinology ◽

10.1210/en.2018-01079 ◽

2019 ◽

Vol 160 (4) ◽

pp. 947-963 ◽

Cited By ~ 1

Author(s):

Mavis A A Tenkorang ◽

Phong Duong ◽

Rebecca L Cunningham

Keyword(s):

Androgen Receptor ◽

Nadph Oxidase ◽

Neuronal Cell ◽

Cell Loss ◽

Receptor Activation ◽

Reduced Form ◽

Negative Effects ◽

Protein Activation ◽

Trisphosphate Receptor

Abstract Oxidative stress (OS) is a common characteristic of several neurodegenerative disorders, including Parkinson disease (PD). PD is more prevalent in men than in women, indicating the possible involvement of androgens. Androgens can have either neuroprotective or neurodamaging effects, depending on the presence of OS. Specifically, in an OS environment, androgens via a membrane-associated androgen receptor (mAR) exacerbate OS-induced damage. To investigate the role of androgens on OS signaling and neurodegeneration, the effects of testosterone and androgen receptor activation on the major OS signaling cascades, the reduced form of NAD phosphate (NADPH) oxidase (NOX)1 and NOX2 and the Gαq/inositol trisphosphate receptor (InsP3R), were examined. To create an OS environment, an immortalized neuronal cell line was exposed to H2O2 prior to cell-permeable/cell-impermeable androgens. Different inhibitors were used to examine the role of G proteins, mAR, InsP3R, and NOX1/2 on OS generation and cell viability. Both testosterone and DHT/3-O-carboxymethyloxime (DHT)–BSA increased H2O2-induced OS and cell death, indicating the involvement of an mAR. Furthermore, classical AR antagonists did not block testosterone’s negative effects in an OS environment. Because there are no known antagonists specific for mARs, an AR protein degrader, ASC-J9, was used to block mAR action. ASC-J9 blocked testosterone’s negative effects. To determine OS-related signaling mediated by mAR, this study examined NOX1, NOX2, Gαq. NOX1, NOX2, and the Gαq complex with mAR. Only NOX inhibition blocked testosterone-induced cell loss and OS. No effects of blocking either Gαq or G protein activation were observed on testosterone’s negative effects. These results indicate that androgen-induced OS is via the mAR–NOX complex and not the mAR–Gαq complex.

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The Neuroprotective Effect of Zingiber cassumunar Roxb. Extract on LPS-Induced Neuronal Cell Loss and Astroglial Activation within the Hippocampus

BioMed Research International ◽

10.1155/2020/4259316 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Ratchaniporn Kongsui ◽

Napatr Sriraksa ◽

Sitthisak Thongrong

Keyword(s):

Proinflammatory Cytokine ◽

Wistar Rats ◽

Single Injection ◽

Neuroprotective Effect ◽

Neuronal Cell ◽

Cell Loss ◽

Neuronal Cell Loss ◽

Male Wistar Rats ◽

Astroglial Activation ◽

Zingiber Cassumunar

The systemic administration of lipopolysaccharide (LPS) has been recognized to induce neuroinflammation which plays a significant role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In this study, we aimed to determine the protective effect of Zingiber cassumunar (Z. cassumunar) or Phlai (in Thai) against LPS-induced neuronal cell loss and the upregulation of glial fibrillary acidic protein (GFAP) of astrocytes in the hippocampus. Adult male Wistar rats were orally administered with Z. cassumunar extract at various doses (50, 100, and 200 mg/kg body weight) for 14 days before a single injection of LPS (250 μg/kg/i.p.). The results indicated that LPS-treated animals exhibited neuronal cell loss and the activation of astrocytes and also increased proinflammatory cytokine interleukin- (IL-) 1β in the hippocampus. Pretreatment with Z. cassumunar markedly reduced neuronal cell loss in the hippocampus. In addition, Z. cassumunar extract at a dose of 200 mg/kg BW significantly suppressed the inflammatory response by reducing the expression of GFAP and IL-1ß in the hippocampus. Therefore, the results suggested that Z. cassumunar extract might be valuable as a neuroprotective agent in neuroinflammation-induced brain damage. However, further investigations are essential to validate the possible active ingredients and mechanisms of its neuroprotective effect.

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A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease

Science Translational Medicine ◽

10.1126/scitranslmed.aau3960 ◽

2020 ◽

Vol 12 (560) ◽

pp. eaau3960

Author(s):

Ibrahim Boussaad ◽

Carolin D. Obermaier ◽

Zoé Hanss ◽

Dheeraj R. Bobbili ◽

Silvia Bolognin ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dysfunction ◽

Neurodegenerative Disorder ◽

Neuronal Cell ◽

Exon Skipping ◽

Cell Loss ◽

Genetically Engineered ◽

Neuronal Precursor Cells

Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.

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