Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

Magi, Simona; Castaldo, Pasqualina; Macrì, Maria Loredana; Maiolino, Marta; Matteucci, Alessandra; Bastioli, Guendalina; Gratteri, Santo; Amoroso, Salvatore; Lariccia, Vincenzo

doi:10.1155/2016/6701324

Cited by 119 publications

(108 citation statements)

References 152 publications

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“…The regulation of intracellular calcium homeostasis is a very complex mechanism that is vital for several cellular pathways and is thus involved in cell survival and death. Two organelles play a major role in calcium homeostasis, the endoplasmic reticulum (ER) and mitochondria, whereas ATPase calcium pump and the sodium-calcium exchanger are the 2 main systems involved in calcium efflux through the plasma membrane [95,96] . Ca 2+ is continuously exchanged between the cytosol and the lumen of the ER.…”

Section: Calcium Homeostasis In Admentioning

confidence: 99%

Molecular Pathogenesis of Alzheimer's Disease: An Update

2017

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Dementia is a chronic or progressive syndrome, characterized by impaired cognitive capacity beyond what could be considered a consequence of normal aging. It affects the memory, thinking process, orientation, comprehension, calculation, learning ability, language, and judgment; although awareness is usually unaffected. Alzheimer's disease (AD) is the most common form of dementia; symptoms include memory loss, difficulty solving problems, disorientation in time and space, among others. The disease was first described in 1906 at a conference in Tubingen, Germany by Alois Alzheimer. One hundred and ten years since its first documentation, many aspects of the pathophysiology of AD have been discovered and understood, however gaps of knowledge continue to exist. This literature review summarizes the main underlying neurobiological mechanisms in AD, including the theory with emphasis on amyloid peptide, cholinergic hypothesis, glutamatergic neurotransmission, the role of tau protein, and the involvement of oxidative stress and calcium.

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Section: Calcium Homeostasis In Admentioning

confidence: 99%

Molecular Pathogenesis of Alzheimer's Disease: An Update

2017

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“…Numerous reviews have detailed critical processes in mitochondria that may be involved in AD and other neurodegenerative diseases [18,52,91,110,113,145]. While discussion of these mechanisms is beyond the scope of this minreview, of particular note is the expanding interest in mitochondria-associated ER membrane (MAM) [3,76,112,130].…”

Section: Emerging Ca2+ Sourcesmentioning

confidence: 99%

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Briggs

Chakroborty

Stutzmann

2017

Biochemical and Biophysical Research Communications

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The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca2+ signaling disruptions, and focus on its role in driving synaptic deficits – which is the feature that does correlate with AD-associated memory loss. Excess Ca2+release from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IP3R and RyR, and the recent emphasis on RyR2. Consistent with ER Ca2+ mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca2+-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.

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“…Nevertheless, accumulated evidence have shown that dysregulation of calcium plays a central role in AD pathogenesis. Perturbation of calcium balance has deleterious consequences for cells and in particular for neurons, leading to necrosis and/or apoptosis and subsequently to stroke and neurodegeneration [4,36,37]. Moreover, different calcium channel blockers have been reported to be effective in preventing long/short-term memory impairment induced by A [25][26][27][28][29][30][31][32][33][34][35] [38].…”

Section: Discussionmentioning

confidence: 99%

Effects of Leptin on Na+/Ca2+ Exchanger in PC12 Cells

Zhang

Sun

et al. 2016

Cell Physiol Biochem

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Background/Aims: Alzheimer's disease (AD) is known to be related to alterations in neuronal intracellular calcium activity ([Ca²⁺]_i). The present study revealed the distinct role of leptin in Na⁺/Ca²⁺-exchanger activity. Methods: [Ca²⁺]_i was determined utilizing Fura-2 fluorescence. The activity of NCX was measured by removal of extracellular Na⁺ in the presence of external Ca²⁺. Na⁺/Ca²⁺-exchanger activity was further quantified from whole cell currents following removal of extracellular Na⁺. Na⁺/Ca²⁺-exchanger isoform NCX1 transcript levels and protein abundance were quantified by RT-PCR and Western blotting, respectively. Results: Exposure of PC12 cells to 30 µM amyloid (Aβ₄₂) increased [Ca²⁺]_i, an effect significantly blunted by 6 hours incubation with leptin before Aβ₄₂ treatment. Moreover, leptin treatment significantly increased Na⁺/Ca²⁺-exchanger mediated Ca+ transport and current, NCX1 transcript level as well as NCX1 membrane protein abundance. Conclusion: We show that leptin blunts Aβ₄₂-evoked [Ca²⁺]_i increase by increasing expression and activity of Na⁺/Ca²⁺-exchanger NCX1.

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Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

Cited by 119 publications

References 152 publications

Molecular Pathogenesis of Alzheimer's Disease: An Update

Molecular Pathogenesis of Alzheimer's Disease: An Update

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Effects of Leptin on Na+/Ca2+ Exchanger in PC12 Cells

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