Amyloid β-protein fragment 25–35 causes activation of cytoplasmic calcium in neurons

doi:10.1016/S0006-291X(05)80044-0

Biochemical and Biophysical Research Communications

Volume 184, Issue 3, 15 May 1992, Pages 1441-1447

https://doi.org/10.1016/S0006-291X(05)80044-0 Get rights and content

The cellular mechanism by which β-amyloid has its effect on neurons is unknown. Based on observations that endogenous neurotoxins, such as glutamate and platelet activating factor (PAF), cause activation of cytoplasmic calcium, we tested if this was true with β-amyloid. Using nerve growth factor-treated PC12 cells, we noted that the active β-amyloid fragment, containing residues 25 to 35, caused a specific and dose-dependent increase in intracellular calcium due to an influx of extracellular calcium.

References (13)

JohnsonP.C. et al.
J Biol Chem
(1985)
BlinksJ.R.
Meth Enzymol
(1989)
ChauhanA et al.
Life Sci
(1991)
SelkoeDJ.
Science
(1990)
Chartier-HarlinM-C et al.
Nature
(1991)
YanknerBA et al.
Science
(1989)

There are more references available in the full text version of this article.

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Citation Excerpt :
One early physiologic action of βAP is an increase in intracellular calcium concentration ([Ca2+]). In nerve growth factor–treated PC12 cells, the increase in [Ca2+] is immediate and dose dependent, which suggests a membrane effect (Joseph and Han 1992). Similarly, some doubling of [Ca2+] is reported in hippocampal primary cultures 24 hours after exposure to aged βAP (25–35) (Mattson et al 1993b; Mogensen et al 1998).
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Citation Excerpt :
A number of mechanisms by which Aβ may exert its toxic effects have been proposed. One of the primary events associated with Aβ toxicity is an increase in intracellular Ca2+ levels and eventual cell death (Joseph & Han, 1992). Some studies have proposed that the insoluble Aβ aggregates may form nonspecific ionic channels in the lipid bilayer, thus increasing the intracellular Ca2+ levels (Arispe et al., 1993; Rhee et al., 1998).
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Amyloid β-protein fragment 25–35 causes activation of cytoplasmic calcium in neurons

J Biol Chem

Meth Enzymol

Life Sci

Science

Nature

Science