Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and strongly associated to aging. AD has been related to excess of neurotoxic oligomers of amyloid β peptide (Aβo), loss of intracellular Ca2+ homeostasis and mitochondrial damage. However, the intimate mechanisms underlying the pathology remain obscure. We have reported recently that long-term cultures of rat hippocampal neurons resembling aging neurons are prone to damage induced by Aβ oligomers (Aβo) while short-term cultured cells resembling young neurons are not. In addition, we have also shown that aging neurons display critical changes in intracellular Ca2+ homeostasis including increased Ca2+ store content and Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria. Aging also promotes the partial loss of store-operated Ca2+ entry (SOCE), a Ca2+ entry pathway involved in memory storage. Here, we have addressed whether Aβo treatment influences differentially intracellular Ca2+ homeostasis in young and aged neurons. We found that Aβo exacerbate the remodeling of intracellular Ca2+ induced by aging. Specifically, Aβo exacerbate the loss of SOCE observed in aged neurons. Aβo also exacerbate the increased resting cytosolic Ca2+ concentration, Ca2+ store content and Ca2+ release as well as increased expression of the mitochondrial Ca2+ uniporter (MCU) observed in aging neurons. In contrast, Aβo elicit none of these effects in young neurons. Surprisingly, we found that Aβo increased the Ca2+ transfer from ER to mitochondria in young neurons without having detrimental effects. Consistently, Aβo increased also colocalization of ER and mitochondria in both young and aged neurons. However, in aged neurons, Aβo suppressed Ca2+ transfer from ER to mitochondria, decreased mitochondrial potential, enhanced reactive oxygen species (ROS) generation and promoted apoptosis. These results suggest that modulation of ER—mitochondria coupling in hippocampal neurons may be a novel physiological role of Aβo. However, excess of Aβo in the face of the remodeling of intracellular Ca2+ homeostasis associated to aging may lead to loss of ER—mitochondrial coupling and AD.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60%–80% of all dementia cases
By using fluorescence Ca2+ imaging of fura-2 loaded cells, we have evaluated the change in the Ca2+ content in the endoplasmic reticulum (ER), store-operated Ca2+ entry (SOCE), the Ca2+ depletion from ER induced by different physiological agonists and the coupling ER-mitochondria, in young (4–8 days in vitro (DIV), short-term) and aged (15–21 DIV, long term) hippocampal neurons cultured in vitro and exposed to amyloid β (Aβ) oligomers (Aβo) as a model of AD and in vitro aging
We tested the effects of Aβ1–42 oligomers (Aβo) on the rate of apoptosis in rat hippocampal neurons cultured for 4–8 DIV representing young neurons, or in neurons cultured for 15–21 DIV that represent many characteristics of aged neurons as reported previously (Calvo-Rodríguez et al, 2016a)
Summary
Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60%–80% of all dementia cases. Recent studies have shown that impaired function of intracellular organelles such as the endoplasmic reticulum (ER) and mitochondria plays an important role in the regulation of Ca2+ during aging and AD (Toescu and Verkhratsky, 2003). In this manner, PSs, located in the membrane of the ER, have been associated to familial AD. The other key player of intracellular Ca2+ homeostasis, mitochondria, are dynamic organelles that generate ATP and contribute to many cellular functions They play a main role in apoptotic signaling, lipid synthesis and buffering of intracellular Ca2+. Dysfunction of mitochondrial bioenergetics (Atamna and Frey, 2007; Yao et al, 2009), increased fission and decreased fusion (Wang et al, 2009; Santos et al, 2010), morphological changes (Hirai et al, 2001; DuBoff et al, 2013; Xie et al, 2013) and redistribution of mitochondria (Kopeikina et al, 2011) have been extensively reported
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