Abstract
Dysregulation of intracellular Ca2+ homeostasis may underlie amyloid β peptide (Aβ) toxicity in Alzheimer's Disease (AD) but the mechanism is unknown. In search for this mechanism we found that Aβ1–42 oligomers, the assembly state correlating best with cognitive decline in AD, but not Aβ fibrils, induce a massive entry of Ca2+ in neurons and promote mitochondrial Ca2+ overload as shown by bioluminescence imaging of targeted aequorin in individual neurons. Aβ oligomers induce also mitochondrial permeability transition, cytochrome c release, apoptosis and cell death. Mitochondrial depolarization prevents mitochondrial Ca2+ overload, cytochrome c release and cell death. In addition, we found that a series of non-steroidal anti-inflammatory drugs (NSAIDs) including salicylate, sulindac sulfide, indomethacin, ibuprofen and R-flurbiprofen depolarize mitochondria and inhibit mitochondrial Ca2+ overload, cytochrome c release and cell death induced by Aβ oligomers. Our results indicate that i) mitochondrial Ca2+ overload underlies the neurotoxicity induced by Aβ oligomers and ii) inhibition of mitochondrial Ca2+ overload provides a novel mechanism of neuroprotection by NSAIDs against Aβ oligomers and AD.
Highlights
Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder due to a massive neuron dysfunction and loss related to development of senile plaques that are made of amyloid b peptide (Ab), a cleavage product of the amyloid precursor protein
This view is supported by the finding that cells responding to Ab1–42 oligomers respond to N-methyl D-aspartate (NMDA) and by immunocytochemical identification of responsive cells
The increases in [Ca2+]cyt induced by Ab1–42 oligomers and the toxic fragment Ab25–35 can be attributed to enhanced entry of extracellular Ca2+ through the plasma membrane rather than release from intracellular Ca2+ stores as they were entirely prevented by removal of extracellular Ca2+
Summary
Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder due to a massive neuron dysfunction and loss related to development of senile plaques that are made of amyloid b peptide (Ab), a cleavage product of the amyloid precursor protein. Neuropathological studies show frequent and varied cerebellar changes in the late stages of the disease [1]. The cerebellum has been shown to be a unique organ in terms of AD manifestations because it is virtually free of neurofibrillary pathology but there is an strong correlation between cerebellar atrophy -with large cell death in the granular layer- and duration and stage of AD [1]. The ‘‘inflammatory hypothesis’’ proposes that Ab may promote a damaging inflammation reaction. This view is supported among other evidence by the neuroprotection afforded by NSAIDs [5]. Ab promotes mitochondrial dysfunction and apoptosis and this toxicity contributes to AD [6] but the mechanism is unclear. Ab may associate with mitochondrial membranes in mutant mice and patients with AD and mitochondria from mutant mice show lower levels of oxygen consumption and reduced respiratory complex-associated enzymatic activity suggesting that mitochondria-bound Ab may impact on mitochondrial activity [7–
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