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Targeting calcium signaling in Alzheimer’s disease: challenges and promising therapeutic avenues
LinLin Song, YongPei Tang, Betty Yuen Kwan Law
2024, 19 (3):
501-502.
doi: 10.4103/1673-5374.380898
The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease (AD): AD is a progressive neurodegenerative disease characterized by cognitive decline, memory impairment, and behavioral changes. With an estimated 50 million people being affected worldwide, the incidence of AD is constantly increasing globally. The hallmark of AD is the accumulation of amyloid-beta protein (Aβ) in the form of amyloid plaques and hyperphosphorylated tau protein in the form of neurofibrillary tangles. However, increasing evidence suggests that calcium ion (Ca2+) dysregulation also plays a crucial role in the pathogenesis of AD (Calvo-Rodriguez and Bacskai, 2021). As a key second messenger, Ca2+ regulates a wide range of cellular processes, including the release of neurotransmitters, gene expression, and cell death. Ca2+ also regulates the activity of Calcium/calmodulin-dependent protein kinase II, which is critical for synaptic plasticity, learning, and memory (Kaushik et al., 2022). Alternation in the Ca2+ signal is an early event in the pathogenesis of AD, which can lead to synaptic dysfunction, neuronal loss, and cognitive impairment. Therefore, dysregulated Ca2+ level has a significant impact on the normal function and survival of neurons. The complex interplay among ion channels, pumps, and exchangers maintains intracellular Ca2+ levels within a steady range in neurons. Voltage-gated Ca2+ channels facilitate Ca2+ entry into the cell, which in turn triggers neurotransmitter release at the presynaptic terminal, allowing electrical signals to propagate throughout the brain. In AD, this delicate balance is disrupted partially via the increased level of Aβ oligomers, resulting in excessive Ca2+ influx into the cytosol, which may initiate a cascade of events ultimately leading to mitochondrial dysfunction and neuronal cell damage. Recent reports have confirmed that several Ca2+ pumps and exchangers responsible for maintaining intracellular Ca2+ balance were altered in AD. For example in the brain of AD patients, the expression and function of plasma membrane Ca2+-ATPase and Na+/Ca2+ exchanger were reduced, leading to elevated levels of intracellular Ca2+ (Calvo-Rodriguez and Bacskai, 2021). It has also been found that aberrant Ca2+ signaling in AD is caused by the over-activation of ryanodine receptors (RyRs) (Lacampagne et al., 2017) or inositol 1,4,5-trisphosphate receptors (Takada et al., 2017) in the endoplasmic reticulum, leading to excessive Ca2+ release into the cytosol. Of note, there are other reported ion channels involved in the progression of AD, including Zn2+, Fe3+, Cu2+ and K+ channel (Wang and Wang, 2017) (Figure 1A). Recent findings support an upstream role for calcium dysregulation in memory decline associated with AD, and clearly implicate that limiting RyR2 opening time prevents and rescues neuronal hyperactivity, memory impairment, and neuronal loss, even in late AD (Yao et al., 2020). Coincidentally, our experiments also confirmed this hypothesis. We found that an increase in Aβ level can cause an elevation of intracellular calcium level by activating RyR2 channels on the endoplasmic reticulum, which further induces mitochondrial dysfunction through the endoplasmic reticulum-mitochondrial signaling cascade leading to neuronal cell damage (Song et al., 2023).
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