Amyloid β Oligomers Increase ER-Mitochondria Ca 2+ Cross Talk in Young Hippocampal Neurons and Exacerbate Aging-Induced Intracellular Ca 2+ Remodeling

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 Ca 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 Ca homeostasis including increased Ca store content and Ca transfer from the endoplasmic reticulum (ER) to mitochondria. Aging also promotes the partial loss of store-operated Ca entry (SOCE), a Ca entry pathway involved in memory storage. Here, we have addressed whether Aβo treatment influences differentially intracellular Ca homeostasis in young and aged neurons. We found that Aβo exacerbate the remodeling of intracellular Ca induced by aging. Specifically, Aβo exacerbate the loss of SOCE observed in aged neurons. Aβo also exacerbate the increased resting cytosolic Ca concentration, Ca store content and Ca release as well as increased expression of the mitochondrial Ca uniporter (MCU) observed in aging neurons. In contrast, Aβo elicit none of these effects in young neurons. Surprisingly, we found that Aβo increased the Ca 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 Ca 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 Ca homeostasis associated to aging may lead to loss of ER-mitochondrial coupling and AD.