Intracellular Injection of Brain Extracts from Alzheimer's Disease Patients Triggers Unregulated Ca 2+ Release from Intracellular Stores That Hinders Cellular Bioenergetics

Strong evidence indicates that amyloid beta (Aβ) inflicts its toxicity in Alzheimer's disease (AD) by promoting uncontrolled elevation of cytosolic Ca in neurons. We have previously shown that synthetic Aβ42 oligomers stimulate abnormal intracellular Ca release from the endoplasmic reticulum stores, suggesting that a similar mechanism of Ca toxicity may be common to the endogenous Aβs oligomers. Here, we use human postmortem brain extracts from AD-affected patients and test their ability to trigger Ca fluxes when injected intracellularly into Xenopus oocytes. Immunological characterization of the samples revealed the elevated content of soluble Aβ oligomers only in samples from AD patients. Intracellular injection of brain extracts from control patients failed to trigger detectable changes in intracellular Ca . Conversely, brain extracts from AD patients triggered Ca events consisting of local and global Ca fluorescent transients. Pre-incubation with either the conformation-specific OC antiserum or caffeine completely suppressed the brain extract's ability to trigger cytosolic Ca events. Computational modeling suggests that these Ca fluxes may impair cells bioenergetic by affecting ATP and ROS production. These results support the hypothesis that Aβ oligomers contained in neurons of AD-affected brains may represent the toxic agents responsible for neuronal malfunctioning and death associated with the disruption of Ca homeostasis.