Role of endoplasmic reticulum Ca2+ signaling in the pathogenesis of Alzheimer disease

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.

Dantrolene, A Treatment for Alzheimer Disease?

“…40,46,47 Therefore, even small fluctuations of Ca 2+ content can significantly change the physiological functions of cells. 39,48-51 …”

“…84,86,87 RYR2 is found in the olfactory nerve layer, dentate gyrus, cerebral cortex, cerebellar granule cells, the facial nucleus and the motor trigeminal nucleus. 39,88 Lastly, RYR3 is highly expressed in the hippocampal CA1 pyramidal cell layer, dorsal thalamus and caudate putamen. 49,85 Overactivation of RYRs in the brain and excessive Ca 2+ release from the ER may result in increased excitatory glutamate release from presynaptic spaces, neuronal death, neurodegeneration, and Aβ pathologies, which is considered as early pathogenic factors in AD (Figure 1).…”

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

“…Numerous literatures have demonstrated that TG2 is up-regulated in various diseases including HD (49, 54, 55, 59-61), AD (37,38,40,42,43,45), and PD (39,44). The splicing mechanism (67, 68) and stress-dependent inductions (34,35,(69)(70)(71)(72) are considered to elucidate the up-regulation, and the increased Ca 2+ levels observed in many diseases (4,(17)(18)(19)(20)(21)(22) are also competent to trigger TG2 activation. The Ca 2+ -dependent activation of TG2 inhibits the IP 3 R1-mediated Ca 2+ release, as revealed in the current study; thus, this enzymatically allosteric modulation should primarily contribute to a negative feedback mechanism to maintain homeostatic control of intracellular Ca 2+ levels.…”

“…Deletion of the genes encoding the type 1 IP 3 R (IP 3 R1) leads to perturbations in long-term potentiation/ depression (3,10,11) and spinogenesis (12), and the human genetic disease spinocerebellar ataxia 15 is caused by haploinsufficiency of the IP 3 R1 gene (13)(14)(15). Dysregulation of IP 3 R1 is also implicated in neurodegenerative diseases including Huntington disease (HD) (16)(17)(18)) and Alzheimer's disease (AD) (19)(20)(21)(22). IP 3 Rs also control fundamental cellular processes-for example, mitochondrial energy production (23,24), autophagy regulation (24)(25)(26)(27), ER stress (28), hepatic gluconeogenesis (29), pancreatic exocytosis (30), and macrophage inflammasomes (31).…”

ER and Golgi stresses increase ER–Golgi SNARE Syntaxin5: Implications for organelle stress and βAPP processing

“…Endoplasmic reticulum (ER) stress occurs under a variety of conditions, such as accumulation of misfolded proteins, perturbation of the secretory pathway, or disruption of Ca 2+ homeostasis [13]. Much attention is given to ER stress because it is especially Abbreviations: A␤ peptide, amyloid-␤ peptide; AD, Alzheimer's disease; BFA, brefeldin A; ␤APP, ␤-amyloid precursor protein; DIV, day in vitro; ELISA, enzyme linked immunosorbent assay; ER, endoplasmic reticulum; SERCA, sarco/endoplasmic reticulum Ca 2+ -ATPase; siRNA, small interfering RNA; SNARE, soluble N-ethylmaleimide-sensitive factor-attachment protein receptor; STS, staurosporine; Syx5, syntaxin 5; Tg, thapsigargin; Tm, tunicamycin.…”