Cytotoxicity of Intracellular Aβ₄₂Amyloid Oligomers Involves Ca²⁺Release from the Endoplasmic Reticulum by Stimulated Production of Inositol Trisphosphate

Abstract

Oligomeric forms of Aβ peptides associated with Alzheimer`s disease (AD) disrupt cellular Ca2+ regulation by liberating Ca2+ into the cytosol from both extracellular and intracellular sources. We elucidated the actions of intracellular Aβ42 by imaging Ca2+ responses to injections of Aβ oligomers into Xenopus oocytes. Two types of signal were observed: (i) local, 'channel-like' transients dependent on extracellular Ca2+ influx, which resembled signals from amlyoid pores formed by extracellular application of oligomers; (ii) local transients and global Ca2+ waves, resembling Ca2+ puffs and waves mediated by inositol trisphosphate (IP3). The latter responses were suppressed by antagonists of the IP3 receptor (caffeine and heparin), by pretreatment with the Gi/o-protein inhibitor pertussis toxin, and by pre-treatment with lithium to deplete membrane inositol lipids. We show that G-protein-mediated stimulation of IP3 production and consequent liberation of Ca2+ from the endoplasmic reticulum by intracellular Aβ oligomers is cytotoxic, potentially representing a novel pathological mechanism in AD which may be further exacerbated by AD-linked mutations in presenilins to promote opening of IP3 receptor/channels.

Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimer’s disease

“…In addition to ER RyR3, inositol 1, 4, 5-triphosphate receptor (IP3R) is also linked to ER Ca 2? release by Ab [74].…”

Astroglial calcium signalling in Alzheimer's disease

“…release from the endoplasmic reticulum (ER) Ca 2+ store [13]. The "β-amyloid calcium pore" hypothesis has evolved into β-amyloid-induced modulation of physiologically-relevant Ca 2+ homeostatic/signalling pathways.…”

Ca2+ dysregulation in the endoplasmic reticulum related to Alzheimer’s disease: A review on experimental progress and computational modeling

“…Costa et al have demonstrated that Ab-induced ER stress can be effectively inhibited by ifenprodil, an antagonist of GluN2B subunits, which could be a potential therapeutic strategy for AD (Costa et al, 2012). Intracellular Ab oligomers are also shown to disrupt Ca 2+ handling of intracellular Ca 2+ stores, especially ERs (Demuro and Parker, 2013). They are believed to be produced from APP residing on the ER and in other intracellular compartments, as well as by uptake from the extracellular space (Mohamed and Posse de Chaves, 2011).…”

“…Ab 42 oligomer pores can also be formed in the membranes of intracellular organelles and result in Ca 2+ leakage into the cytosol; the disruption is comparatively mild (Demuro et al, 2005;Demuro and Parker, 2013). Most research has demonstrated that Ab oligomers enhance Ca 2+ liberation from the ER, mainly by altering Ca 2+ release via IP 3 Rs and RyRs (Kelliher et al, 1999;Ferreiro et al, 2004;Stutzmann et al, 2006;Schapansky et al, 2007).…”

“…Ab oligomers can bind to cellular prion proteins and active mGluR5, which may also lead to increased production of IP 3 (Um et al, 2013). In addition, recent research has reported that intracellular Ab 42 oligomers induce Ca 2 + liberation from the ER via IP 3 Rs by stimulating PLC-mediated IP 3 production in Xenopus oocytes (Demuro and Parker, 2013). Another study demonstrated that Ab 42 -induced Ca 2+ release from ER may mostly depend on activating PLC and, subsequent, IP 3 generation rather than by direct interaction with IP 3 Rs (Allan et al, 2013).…”