The Eighth ECS Workshop on “Calcium Signaling in Aging and Neurodegenerative Diseases”

Parys, Jan B.; Pereira, Cláudia; Alonso, Carlos

doi:10.3390/ijms20246263

Cited by 3 publications

(2 citation statements)

References 12 publications

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“…Strong evidence supports the involvement of intracellular Ca 2+ dyshomeostasis in aging and neurodegenerative disorders including AD ( 19 ). Our group, and others, have recently shown that long-term cultures of rat hippocampal neurons display characteristics of aged neurons ( 20 – 22 ).…”

Section: Tlr4 and Calcium Signaling In Alzheimer’s Diseasementioning

confidence: 78%

Role of Toll Like Receptor 4 in Alzheimer’s Disease

et al. 2020

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Long-term evidence has confirmed the involvement of an inflammatory component in neurodegenerative disorders including Alzheimer’s disease (AD). This view is supported, in part, by data suggesting that selected non-steroidal anti-inflammatory drugs (NSAIDs) provide protection. Additionally, molecular players of the innate immune system have recently been proposed to contribute to these diseases. Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system that recognize different pathogen-derived and tissue damage-related ligands. TLR4 mediated signaling has been reported to contribute to the pathogenesis of age-related neurodegenerative diseases, including AD. Although the pathophysiology of AD is not clear, soluble aggregates (oligomers) of the amyloid β peptide (Aβo) have been proven to be key players in the pathology of AD. Among others, Aβo promote Ca 2+ entry and mitochondrial Ca 2+ overload leading to cell death in neurons. TLR4 has recently been found to be involved in AD but the mechanisms are unclear. Our group recently reported that lipopolysaccharide (LPS), a TLR4 receptor agonist, increases cytosolic Ca 2+ concentration leading to apoptosis. Strikingly, this effect was only observed in long-term cultured primary neurons considered a model of aging neurons, but not in short-term cultured neurons resembling young neurons. These effects were significantly prevented by pharmacological blockade of TLR4 receptor signaling. Moreover, TLR4 expression in rat hippocampal neurons increased significantly in aged neurons in vitro . Therefore, molecular patterns associated with infection and/or brain cell damage may activate TLR4 and Ca 2+ signaling, an effect exacerbated during neuronal aging. Here, we briefly review the data regarding the involvement of TLR4 in AD.

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Section: Tlr4 and Calcium Signaling In Alzheimer’s Diseasementioning

confidence: 78%

Role of Toll Like Receptor 4 in Alzheimer’s Disease

et al. 2020

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“…In the last few years, a large body of evidence indicates that changes in intracellular Ca 2+ homeostasis may contribute to neuron damage in AD and PD. [156] Early evidence suggested that neurons obtained from mouse models of AD displayed changes in intracellular Ca 2+ homeostasis, including alterations in resting levels of intracellular Ca 2+ and Ca 2+ stores. [157] These changes could be associated to the effects of mutations in the APP and presenilins PS1 and PS2, which process APP either directly or indirectly via excessive production of Aβ species.…”

Section: Ca 2+ Dysregulation and Downstream Effects In Alzheimer's Di...mentioning

confidence: 99%

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

Tapias¹,

González-Andrés²,

Peña³

et al. 2023

Preprint

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The brain is a complex organ that controls body functions and homeostasis through the action of neuronal and glial cells. Neuronal activity is highly energy-dependent and requires large numbers of functional mitochondria to provide substantial amount of energy via mitochondrial oxidative phosphorylation (OXPHOS), the most efficient metabolic process to generate adenosine triphosphate (ATP). Under stress conditions, neurons are particularly vulnerable to mitochondrial dysfunction, leading to decreased ATP synthesis, excessive generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and intracellular Ca2+ dyshomeostasis, although not necessarily in this order. Alzheimer's disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases in elderly and are characterized by the presence of abnormal protein aggregates and the progressive and irreversible loss of neurons in specific brain regions. The exact mechanisms underlying the etiopathogenesis of AD or PD remain unknown, but there is extensive evidence indicating that compromised mitochondrial energy metabolism along with a depleted antioxidant system play a vital role in the pathophysiology of these neurological disorders. Toxic accumulation of proteins such as amyloid β peptides (Aβ) or amyloid precursor protein (APP) in AD and α-synuclein (α-syn) or leucine-rich repeat kinase 2 (LRRK2) in PD cause mitochondrial deficits through direct inhibition of electron transport chain (ETC) assembly and function, thereby resulting in further generation of ROS/RNS and disturbance of Ca2+ influx. Due to the improvement in life expectancy, the incidence of age-related neurodegenerative diseases has significantly increased. There is no effective protective treatment or therapy available but rather only very limited palliative treatment. There is an urgent need for the development of preventive strategies and disease-modifying therapies (both neuroprotective and neurorestorative interventions) to treat AD/PD. Here, we review the capability of some heterocyclic compounds to modulate Ca2+ homeostasis and signaling with a potential role in regulating mitochondrial function and associated free radical production during the development and onset of AD or PD. Moreover, we have included the chemical synthesis of a series of heterocycles and their derivatives.

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PPP3R1 Promotes MSCs Senescence by Inducing Plasma Membrane Depolarization and Increasing Ca2+ Influx

Gong

Chen

et al. 2023

IJMS

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Aging of mesenchymal stem cells(MSCs) has been widely reported to be strongly associated with aging-related diseases, including osteoporosis (OP). In particular, the beneficial functions of mesenchymal stem cells decline with age, limiting their therapeutic efficacy in age-related bone loss diseases. Therefore, how to improve mesenchymal stem cell aging to treat age-related bone loss is the current research focus. However, the underlying mechanism remains unclear. In this study, protein phosphatase 3, regulatory subunit B, alpha isoform, calcineurin B, type I (PPP3R1) was found to accelerate the senescence of mesenchymal stem cells, resulting in reduced osteogenic differentiation and enhanced adipogenic differentiation in vitro. Mechanistically, PPP3R1 induces changes in membrane potential to promote cellular senescence by polarizing to depolarizing, increasing Ca2+ influx and activating downstream NFAT/ATF3/p53 signaling. In conclusion, the results identify a novel pathway of mesenchymal stem cell aging that may lead to novel therapeutic approaches for age-related bone loss.

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The Eighth ECS Workshop on “Calcium Signaling in Aging and Neurodegenerative Diseases”

Cited by 3 publications

References 12 publications

Role of Toll Like Receptor 4 in Alzheimer’s Disease

Role of Toll Like Receptor 4 in Alzheimer’s Disease

Therapeutic Potential of Heterocyclic Compounds Targeting Mitochondrial Calcium Homeostasis and Signaling in Alzheimer’s Disease and Parkinson’s Disease

PPP3R1 Promotes MSCs Senescence by Inducing Plasma Membrane Depolarization and Increasing Ca2+ Influx

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