Abeta42 oligomers selectively disrupt neuronal calcium release

Accumulation of amyloid-b (Ab) peptides correlates with aging and progression of Alzheimer's disease (AD). Ab peptides, which cause early synaptic dysfunctions, spine loss, and memory deficits, also disturb intracellular Ca2þ homeostasis. By cytosolic and endoplasmic reticulum Ca2þ measurements, we here define the short-term effects of synthetic Ab42 on neuronal Ca2þ dynamics. When applied acutely at submicromolar concentration, as either oligomers or monomers, Ab42 did not cause Ca2þ release or Ca2þ influx. Similarly, 1-hour treatment with Ab42 modified neither the resting cytosolic Ca2þ level nor the long-lasting Ca2þ influx caused by KCl-induced depolarization. In contrast, Ab42 oligomers, but not monomers, significantly altered Ca2þ release from stores with opposite effects on inositol 1,4,5-trisphosphate (IP3)- and caffeine-induced Ca2þ mobilization without alteration of the total store Ca2þ content. Ca2þ dysregulation by Ab42 oligomers involves metabotropic glutamate receptor 5 and requires network activity and the intact exo-endocytotic machinery, being prevented by tetrodotoxin and tetanus toxin. These findings support the idea that Ca2þ store dysfunction is directly involved in Ab42 neurotoxicity and represents a potential therapeutic target in AD-like dementia