Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2

Galla, Luisa; Redolfi, Nelly; Pozzan, Tullio; Pizzo, Paola; Greotti, Elisa

doi:10.3390/ijms21030770

Cited by 45 publications

(34 citation statements)

References 219 publications

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“…In conclusion, here, we showed that, in Aβ-secreting neuroglioma cells, downregulation of ORAI2 potentiates SOCE without altering the store Ca 2+ content and decreases the Aβ42/Aβ40 ratio thus being an interesting tool to restore defective Ca 2+ entry associated to AD [ 9 , 10 , 54 , 76 ], while preventing amyloid seeding, given the direct correlation of this latter with the Aβ42/Aβ40 ratio. Altogether, our data support the idea that SOCE, and particularly ORAI2, could be a potential therapeutic target in AD.…”

Section: Discussionmentioning

confidence: 68%

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: Discussionmentioning

confidence: 68%

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

Scremin

Agostini

Leparulo

et al. 2020

IJMS

Self Cite

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“…Finally, it is becoming increasingly clear that also altered intracellular Ca 2+ responses are a common feature in AD, especially in cases of familial mutations in the genes encoding APP or the γ-secretase/presenilin1 and 2 (PS1/PS2) (reviewed in [ 290 , 291 ]). However, the pathogenic mechanisms through which mutations in APP and PSs affect intracellular Ca 2+ are not fully understood [ 292 ].…”

Section: Alterations Of Camp Compartmentalization In Neurodegeneramentioning

confidence: 99%

Compartmentalized Signaling in Aging and Neurodegeneration

Benedetto

Iannucci

Surdo

et al. 2021

Cells

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The cyclic AMP (cAMP) signalling cascade is necessary for cell homeostasis and plays important roles in many processes. This is particularly relevant during ageing and age-related diseases, where drastic changes, generally decreases, in cAMP levels have been associated with the progressive decline in overall cell function and, eventually, the loss of cellular integrity. The functional relevance of reduced cAMP is clearly supported by the finding that increases in cAMP levels can reverse some of the effects of ageing. Nevertheless, despite these observations, the molecular mechanisms underlying the dysregulation of cAMP signalling in ageing are not well understood. Compartmentalization is widely accepted as the modality through which cAMP achieves its functional specificity; therefore, it is important to understand whether and how this mechanism is affected during ageing and to define which is its contribution to this process. Several animal models demonstrate the importance of specific cAMP signalling components in ageing, however, how age-related changes in each of these elements affect the compartmentalization of the cAMP pathway is largely unknown. In this review, we explore the connection of single components of the cAMP signalling cascade to ageing and age-related diseases whilst elaborating the literature in the context of cAMP signalling compartmentalization.

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“…Calcium overload has also been correlated with disrupted neuronal structure and function ( Kuchibhotla et al , 2008 ). Recent efforts investigate the calcium dysregulation in order to find additional pathogenic mechanisms and new treatment methods for AD ( Alvarez et al , 2020 ; Dave and Jha, 2020 ; Galla et al , 2020 ). Several therapeutic drugs that currently target plasma Ca2+ channels have received good efficacy on in vitro and in vivo AD models.…”

Section: Discussionmentioning

confidence: 99%

PathWalks: identifying pathway communities using a disease-related map of integrated information

et al. 2020

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Abstract Motivation Understanding the underlying biological mechanisms and respective interactions of a disease remains an elusive, time consuming and costly task. Computational methodologies that propose pathway/mechanism communities and reveal respective relationships can be of great value as they can help expedite the process of identifying how perturbations in a single pathway can affect other pathways. Results We present a random-walks-based methodology called PathWalks, where a walker crosses a pathway-to-pathway network under the guidance of a disease-related map. The latter is a gene network that we construct by integrating multi-source information regarding a specific disease. The most frequent trajectories highlight communities of pathways that are expected to be strongly related to the disease under study. We apply the PathWalks methodology on Alzheimer's disease and idiopathic pulmonary fibrosis and establish that it can highlight pathways that are also identified by other pathway analysis tools as well as are backed through bibliographic references. More importantly, PathWalks produces additional new pathways that are functionally connected with those already established, giving insight for further experimentation. Availability and implementation https://github.com/vagkaratzas/PathWalks. Supplementary information Supplementary data are available at Bioinformatics online.

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Intracellular Calcium Dysregulation by the Alzheimer’s Disease-Linked Protein Presenilin 2

Cited by 45 publications

References 219 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

Compartmentalized Signaling in Aging and Neurodegeneration

PathWalks: identifying pathway communities using a disease-related map of integrated information

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