Abstract
Alzheimer disease (AD) is a major threat of twenty-first century that is responsible for the majority of dementia in the elderly. Development of effective AD-preventing therapies are the top priority tasks for neuroscience research. Amyloid hypothesis of AD is a dominant idea in the field, but so far all amyloid-targeting therapies have failed in clinical trials. In addition to amyloid accumulation, there are consistent reports of abnormal calcium signaling in AD neurons. AD neurons exhibit enhanced intracellular calcium (Ca2+) liberation from the endoplasmic reticulum (ER) and reduced store-operated Ca2+ entry (SOC). These changes occur primarily as a result of ER Ca2+ overload. We argue that normalization of intracellular Ca2+ homeostasis could be a strategy for development of effective disease-modifying therapies. The current review summarizes recent data about changes in ER Ca2+ signaling in AD. Ca2+ channels that are discussed in the current review include: inositol trisphosphate receptors, ryanodine receptors, presenilins as ER Ca2+ leak channels, and neuronal SOC channels. We discuss how function of these channels is altered in AD and how important are resulting Ca2+ signaling changes for AD pathogenesis.
Highlights
Calcium (Ca2+) is one of the most important second messengers in the nervous system
Neurons are highly susceptible to any changes in intracellular Ca2+ concentrations: insufficient intracellular Ca2+ content lead to abnormal functioning of neurons, whereas excessive Ca2+ levels cause cell death (Berridge, 1998)
Opposite conclusion was obtained by our laboratory in experiments with APPPS1 transgenic mouse model (Thy1-APPKM670/671NL, Thy1-PS1L166P; Zhang et al, 2010b). In these studies we discovered that long-term oral feeding of dantrolene exacerbated plaque formation and resulted in loss of hippocampal synaptic markers and neuronal deterioration in 8-month-old APPPS1 mice (Zhang et al, 2010b)
Summary
Calcium (Ca2+) is one of the most important second messengers in the nervous system. Ca2+-mediated signal transduction connects membrane excitability and biological functions of neurons ranging from proliferation, secretion, gene expression, ATP production, cell death to memory formation and its loss. Acting at the border of electrical and signaling “worlds” of the cell, Ca2+-permeable channels play a major role in many key aspects of neuronal functions. Due to the huge importance of the calcium as the second messenger neurons utilize many approaches to regulate intracellular Ca2+ content, mainly via local signal transduction pathways. Neuronal Ca2+ influx can be maintained by different Ca2+-permeable channels, such as voltage-gated Ca2+ channels of plasma membrane, N -methyl-D-aspartate (NMDA) receptors, αamino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptors, nicotinic receptors, store-operated Ca2+ channels (SOC). Mitochondria play an important role in intracellular Ca2+ handling. Even small fluctuations in Ca2+ content can be very detrimental over long life of a neuron (Khachaturian, 1989)
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