Restoring Calcium Homeostasis to Treat Alzheimer’s Disease: A Future Perspective

Попугаева, Елена; Власова, О. Л.; Bezprozvanny, Ilya

doi:10.2217/nmt.15.36

Cited by 28 publications

(23 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Impeding of Ca 2+ homeostasis leads to impairment of neuronal activity, neurogenesis, and neurotransmitter release that causes the progression of pathogenesis of AD and also induces mitochondrial apoptotic cascade . We measured intracellular free Ca 2+ by fluorescent Ca 2+ indicator, Fura‐2AM after incubation of cells with Aβ 40 (10 μ m ) alone or co‐incubated with BSBHp (3 μ m ).…”

Section: Resultsmentioning

confidence: 99%

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Kumar¹,

Paul

Kalita

et al. 2016

Chem Biol Drug Des

View full text Add to dashboard Cite

Alzheimer's disease is most common neurodegenerative disorder and is characterized by increased production of soluble amyloid-β oligomers, the main toxic species predominantly formed from aggregation of monomeric amyloid-β (Aβ). Increased production of Aβ invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. This study was aimed to investigate the neuroprotective effects of a β-sheet breaker α/β-hybrid peptide (BSBHp) and the underlying mechanisms against Aβ -induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with the peptide Aβ to induce neurotoxicity. Assays for cell viability, cell membrane damage, cellular apoptosis, generation of reactive oxygen species (ROS), intracellular free Ca , and key apoptotic protein levels were performed in vitro. Our results showed that pretreatment with BSBHp significantly attenuates Aβ -induced toxicity by retaining cell viability, suppressing generation of ROS, Ca levels, and effectively protects neuronal apoptosis by suppressing pro-apoptotic protein Bax and up-regulating antiapoptotic protein Bcl-2. These results suggest that α/β-hybrid peptide has neuroprotective effects against Aβ -induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases.

show abstract

Section: Resultsmentioning

confidence: 99%

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Kumar¹,

Paul

Kalita

et al. 2016

Chem Biol Drug Des

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 74%

“…Downregulation of STIM2 proteins was observed in cells from AD patients and in AD mouse models [19,21]. Based on these results we suggested that nSOC-mediated Ca 2+ influx is needed to maintain continuous activity of CaMKII in the spines, supporting stability of mushroom spines [19,22].As it is clear from this brief summary, we are still trying to understand the roles of STIM1 and STIM2 proteins in neurons. Some groups suggest that in neurons STIM1 and STIM2 proteins function in SOC-independent manner [9][10][11].…”

mentioning

confidence: 84%

STIM Proteins As Regulators of Neuronal Store-Operated Calcium Influx

Попугаева

Bezprozvanny

2018

Neurodegener. Dis. Manag.

Self Cite

View full text Add to dashboard Cite

The store-operated calcium channels (SOC) were initially described in nonexcitable cells, such as T cells in the immune system [1]. In neurons, the presence of SOC has been controversial [2]. The main argument against neuronal SOC (nSOC) is that neurons possess many other calcium-permeable channels with high conductance, such as NMDA receptors and voltage-gated calcium channels. The existence, functional relevance and molecular identity of nSOC are still under investigation. However, recent molecular analysis of nSOC provided support to its existence and importance for neuronal function.SOC is mediated by two main components: endoplasmic reticulum (ER) Ca 2+ sensors STIM1 or STIM2 proteins [3] and plasma membrane (PM) Ca 2+ channels from Orai and TRPC protein families [1]. SOC in nonexcitable cells is activated by ER Ca 2+ depletion in response to activation of inositol (1,4,5)-trisphosphate receptors and Ca 2+ release from the ER. ER Ca 2+ concentration is sensed by helix-loop-helix structural domain (EF hand domain) in the luminal portion of STIM1. Following Ca 2+ depletion from the ER, STIM1 forms oligomers and translocates to ER-PM junctions [1]. Once located to ER-PM junctions, STIM1 binds to Orai proteins and activate SOC Ca 2+ influx, leading to an increase in intracellular Ca 2+ concentration. This cytoplasmic Ca 2+ abundance is sequestered by SERCA pump to the ER, refilling the stores. The EF hand domain of STIM2 proteins has significantly lower affinity for Ca 2+ than STIM1, and it has been established that STIM2 proteins primarily control steady-state ER and cytosolic Ca 2+ homeostasis [4]. Both STIM1 and STIM2 proteins are expressed in hippocampal neurons [5], and both of these proteins have been implicated in control of nSOC. Klejman et al. observed that STIM1 is colocalized with Orai1 upon depletion of Ca 2+ stores in dendrites and soma [6]. More recent reports suggested that STIM1 and Orai1 are colocalized and may interact with synaptopodin, a protein that regulates synaptic plasticity in hippocampal dendritic spines [7]. Activation of STIM1 and nSOC was described in hippocampal neurons following activation of type I metabotropic glutamate receptors (mGluR) or muscarinic acetylcholine receptors (mAChR) [8]. Notably, nSOC-independent functions of STIM1 in hipocampal neurons were also reported. It was suggested that STIM1 directly controls level of phosphorylation and surface expression of the AMPAR [9]. The role of STIM1 in control of neuronal L-type Ca 2+ channel activity [10] and feedback regulation of Ca 2+ signals in presynaptic terminals was reported [11]. Using optically controlled construct OptoSTIM1, Kyung et al. demonstrated that expression and activation of this construct in mouse hippocampus is able to induce nSOC Ca 2+ influx and promote contextual memory formation [12]. Majewski et al. observed improvements of contextual learning in STIM1 overexpressing mice [13]. These authors further demonstrated that overexpression of STIM1 does not influence long-term potentiaton (LTP) induction in...

show abstract

“…Nobody can at present answer this question. Several possibilities have been advanced over the years, e.g., a prominent role for Ca 2+ -dyshomeostasis and neurotoxicity (64,66,67), but both remain subject for debate.…”

Section: The Situation In Alzheimer's Sick Brain Cells: Partially Simmentioning

confidence: 99%

Intraluminal Farnesol and Farnesal in the Mealworm's Alimentary Canal: An Unusual Storage Site Uncovering Hidden Eukaryote Ca2+-Homeostasis-Dependent “Golgicrine” Activities

Loof

Schoofs

2019

Front. Endocrinol.

View full text Add to dashboard Cite

Farnesol, the sesquiterpenoid precursor of the six presently known insect juvenile hormones (JHs) was for the first time chemically identified in 1961, not in JH synthesizing glands or whole body extracts, but in excrements of the mealworm Tenebrio molitor. This finding was thought to be irrelevant and remained unexplored. In 1970, it was reported that the fall to zero of the JH titer in both prediapausing adults and in last instar larvae of the Colorado potato beetle causes severe malfunctioning of the Golgi system in the fat body, among various other effects. This endomembrane system in the cytoplasm resides at the intersection of the secretory, lysosomal, and endocytic pathways and is required for the processing of secretory proteins. Why the Golgi needs farnesol-like endogenous sesquiterpenoids (FLS) for its proper functioning has also never been further investigated. In 1999, farnesol was found to be a natural endogenous ligand for particular types of voltage-gated Ca 2+ channels in mammalian cells, a finding that also remained undervalued. Only since 2014 more attention has been paid to the functional research of the "noble unknown" farnesol, in particular to its Ca 2+-homeostasis-related juvenilizing and anti-apoptotic activities. Here, we introduce the term "Golgicrine activity" that addresses the secretory activity of the RER-Golgi system from its role in Ca 2+-homeostasis rather than from its conventional role in mere protein secretion. Golgicrine activity attributes the so far forgotten role of farnesol-like sesquiterpenoids in proper Golgi functioning, and unites the endocrine, exocrine and enterocrine functions of these sesquiterpenoids. This out of the box view may open novel perspectives for the better understanding of particular inflammatory bowel diseases and of neurodegenerative diseases as well, because the early initiation of Alzheimer's disease may possibly result from malfunctioning of the mevalonate-farnesol-cholesterol biosynthetic pathway and thus might be a farnesol-and Ca 2+-homeostasis-dependent Golgicrine issue.

show abstract

Restoring Calcium Homeostasis to Treat Alzheimer’s Disease: A Future Perspective

Cited by 28 publications

References 26 publications

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

Protective effects of β‐sheet breaker α/β‐hybrid peptide against amyloid β‐induced neuronal apoptosis in vitro

STIM Proteins As Regulators of Neuronal Store-Operated Calcium Influx

Intraluminal Farnesol and Farnesal in the Mealworm's Alimentary Canal: An Unusual Storage Site Uncovering Hidden Eukaryote Ca2+-Homeostasis-Dependent “Golgicrine” Activities

Contact Info

Product

Resources

About