Cellular consequences of the expression of Alzheimer's disease-causing presenilin 1 mutations in human neuroblastoma (SH-SY5Y) cells

Boyle, John P.; Hettiarachchi, Nishani T.; Wilkinson, Jenny A.; Pearson, Hugh A.; Scragg, Jason L.; Lendon, Corinne; Al‐Owais, Moza M.; Kim, Cindy B.; Myers, D.; Warburton, Philip; Peers, Chris

doi:10.1016/j.brainres.2011.12.061

Cited by 8 publications

(7 citation statements)

References 47 publications

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“…In AD patients as well as in AD mouse models, the stoichiometric ratio between the two variants is altered, favouring the longer version, which is more prone to oligomerisation and deposition [ 3 , 5 ]. Further investigations on the pleiotropic roles of presenilins, led to the discovery of their effect on cellular Ca 2+ handling: specifically, when mutated, they alter the endoplasmic reticulum (ER) Ca 2+ content as well as the related refilling mechanism, known as SOCE [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Aβ accumulation was variably suggested to be a Ca 2+ -sensitive event, with SOCE playing a primary role.…”

Section: Introductionmentioning

confidence: 99%

ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells

Scremin

Agostini

Leparulo

et al. 2020

IJMS

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Senile plaques, the hallmarks of Alzheimer’s Disease (AD), are generated by the deposition of amyloid-beta (Aβ), the proteolytic product of amyloid precursor protein (APP), by β and γ-secretase. A large body of evidence points towards a role for Ca2+ imbalances in the pathophysiology of both sporadic and familial forms of AD (FAD). A reduction in store-operated Ca2+ entry (SOCE) is shared by numerous FAD-linked mutations, and SOCE is involved in Aβ accumulation in different model cells. In neurons, both the role and components of SOCE remain quite obscure, whereas in astrocytes, SOCE controls their Ca2+-based excitability and communication to neurons. Glial cells are also directly involved in Aβ production and clearance. Here, we focus on the role of ORAI2, a key SOCE component, in modulating SOCE in the human neuroglioma cell line H4. We show that ORAI2 overexpression reduces both SOCE level and stores Ca2+ content, while ORAI2 downregulation significantly increases SOCE amplitude without affecting store Ca2+ handling. In Aβ-secreting H4-APPswe cells, SOCE inhibition by BTP2 and SOCE augmentation by ORAI2 downregulation respectively increases and decreases Aβ42 accumulation. Based on these findings, we suggest ORAI2 downregulation as a potential tool to rescue defective SOCE in AD, while preventing plaque formation.

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Section: Introductionmentioning

confidence: 99%

ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells

Scremin

Agostini

Leparulo

et al. 2020

IJMS

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“…Here, we use an in vitro model, the SH-SY5Y cell line that can be differentiated to assume a neuronal morphology and phenotype. SH-SY5Y cells are widely used in the AD field (Boyle et al, 2012;Koriyama et al, 2015;Oguchi et al, 2017;Pascual-Caro et al, 2018;Shang et al, 2019). Their ability to be differentiated makes them appealing because they phenotypically and molecularly mimic primary neurons after going through the differentiation process (Gimenez-Cassina et al, 2006;Cheung et al, 2009;Agholme et al, 2010;Xie et al, 2010;Shipley et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Loss of DEK Expression Induces Alzheimer’s Disease Phenotypes in Differentiated SH-SY5Y Cells

Greene

Parks

Solomon

et al. 2020

Front. Mol. Neurosci.

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Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by the buildup of β-amyloid plaques and neurofibrillary Tau tangles. This leads to decreased synaptic efficacy, cell death, and, consequently, brain atrophy in patients. Behaviorally, this manifests as memory loss and confusion. Using a gene ontology analysis, we recently identified AD and other age-related dementias as candidate diseases associated with the loss of DEK expression. DEK is a nuclear phosphoprotein with roles in DNA repair, cellular proliferation, and inhibiting apoptosis. Work from our laboratory determined that DEK is highly expressed in the brain, particularly in regions relevant to learning and memory, including the hippocampus. Moreover, we have also determined that DEK is highly expressed in neurons. Consistent with our gene ontology analysis, we recently reported that cortical DEK protein levels are inversely proportional to dementia severity scores in elderly female patients. However, the functional role of DEK in neurons is unknown. Thus, we knocked down DEK in an in vitro neuronal model, differentiated SH-SY5Y cells, hypothesizing that DEK loss would result in cellular and molecular phenotypes consistent with AD. We found that DEK loss resulted in increased neuronal death by apoptosis (i.e., cleaved caspases 3 and 8), decreased β-catenin levels, disrupted neurite development, higher levels of total and phosphorylated Tau at Ser262, and protein aggregates. We have demonstrated that DEK loss in vitro recapitulates cellular and molecular phenotypes of AD pathology.

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“…However, the aggressiveness of a given mutation is better reflected by the increase in Aβ 42 levels and the Aβ 42 /Aβ 40 ratio [10,49], which are inversely correlated with the age at onset in familial AD [50]. With respect to the S170F mutation, in vitro investigations have consistently demonstrated that it results in a marked, approximately threefold increase in Aβ 42 production [43,51,52] and, with variations across publications due to methodological differences, an elevated Aβ 42 /Aβ 40 ratio as well [51]. It should be noted that these results were obtained from in vitro investigations or animal studies so that it remains to be determined how they relate to the measurement of Aβ CSF levels in patients.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1

et al. 2018

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Background: In rare cases, patients with Alzheimer disease (AD) present at an early age and with a family history suggestive of an autosomal dominant mode of inheritance. Mutations of the presenilin-1 (PSEN1) gene are the most common causes of dementia in these patients. Early-onset and particularly familial AD patients frequently present with variable non-amnestic cognitive symptoms such as visual, language or behavioural changes as well as non-cognitive, e.g. motor, symptoms. Objective: To investigate the phenotypic variability in carriers of the PSEN1 S170F mutation. Methods: We report a family with 4 patients carrying the S170F mutation of whom 2 underwent detailed clinical examinations. We discuss our current findings in the context of previously reported S170F cases. Results: The clinical phenotype was consistent regarding initial memory impairment and early onset in the late twenties found in all S170F patients. There were frequent non-amnestic cognitive changes and, at early stages of the disease, indications of a more pronounced disturbance of visuospatial abilities as compared to face and object recognition. Non-cognitive symptoms most often included myoclonus and cerebellar ataxia. A review of the available case reports indicates some phenotypic variability associated with the S170F mutation including different constellations of symptoms such as parkinsonism and delusions. Conclusion: The variable clinical findings associated with the S170F mutation highlight the relevance of atypical phenotypes in the context of research and under a clinical perspective. CSF sampling and detection of Aβ species may be essential to indicate AD pathology in unclear cases presenting with cognitive and motor symptoms at a younger age.

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Cellular consequences of the expression of Alzheimer's disease-causing presenilin 1 mutations in human neuroblastoma (SH-SY5Y) cells

Cited by 8 publications

References 47 publications

ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells

ORAI2 Down-Regulation Potentiates SOCE and Decreases Aβ42 Accumulation in Human Neuroglioma Cells

Loss of DEK Expression Induces Alzheimer’s Disease Phenotypes in Differentiated SH-SY5Y Cells

Phenotypic Variability in Autosomal Dominant Familial Alzheimer Disease due to the S170F Mutation of Presenilin-1

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