Regulation of intracellular calcium in cortical neurons transgenic for human Abeta40 and Abeta42 following nutritive challenge.
The pathogenesis of Alzheimer's Disease (AD) is not fully understood. Amyloid plaques could be causally linked to neuronal loss in AD. Two proteolytic products of the Amyloid Precursor Protein (APP), Amyloid beta40 (Abeta40) and Amyloid beta42 (Abeta42), are considered to be critical in the neurodegeneration seen in AD. However, in transgenic mice that overexpress human Abeta40 or Abeta42, it was shown that Abeta42 was much more amyloidogenic than Abeta40. In contrast to this observation, we have found that cultured cortical neurons from mice transgenic for human Abeta40 and for Abeta42 are both and statistically equally vulnerable to nutritive challenge induced by trophic factor withdrawal (TFW). Aberrant regulation of InsP(3)R (Inositol triphosphate receptor)-mediated calcium release has been implicated in neuronal cell death. It is however not clear whether this pathway plays a critical role in cortical neurons transgenic for different species of human Abeta. We now report that Abeta40 and Abeta42 equally exacerbated intracellular calcium response to TFW in cortical neurons following TFW. When bradykinin (BK), a potent stimulant of InsP(3)R-mediated calcium release from ER, was applied to these cells, wild-type (WT) neurons exhibited a steep rise in [Ca(2+)](i) but this was not observed in either Abeta transgenic type. Similarly, when 1 muM Xestopongin C (XeC), a specific blocker of InsP(3)R, was applied to these neurons, WT cells showed a significant attenuation of increase in [Ca(2+)](i) following TFW, while elevation in [Ca(2+)](i) induced by TFW remained largely unchanged in Abeta40 and Abeta42 cells. Finally, when we treated these cells with a Ca(2+) chelator (BAPTA; 10 muM), all three cell types had a marked attenuation of [Ca(2+)](i). These findings indicate that the exacerbated calcium dysregulation following TFW in Abeta transgenic neurons are likely to be mediated by calcium channels other than ER InsP3R receptors. Overall, our results also suggest that a highly amyloidogenic Abeta species, such as Abeta42, might not necessarily be significantly more neurotoxic than a less or non-amyloidogenic Abeta species, such as Abeta40.
Shirwany
Najeeb A
NA
Department of Physiology, University of Oklahoma Health Sciences Center Oklahoma City, OK 73014, USA.
Xie
Jun
J
Guo
Qing
Q
J Biol Chem. 2002 Sep 13;277(37):34287-94
12097332
Neuron. 2005 Jul 21;47(2):191-199
16039562
J Neurochem. 1999 Mar;72(3):1061-8
10037477
Int J Clin Exp Pathol. 2009;2(4):339-52
19158991
Eur J Neurosci. 2003 Mar;17(6):1189-96
12670307
J Neurochem. 1999 Mar;72(3):1030-9
10037474
J Neuropathol Exp Neurol. 1986 Nov;45(6):647-64
3772397
Biochem Biophys Res Commun. 1984 May 16;120(3):885-90
6375662
Nature. 2000 Jan 6;403(6765):98-103
10638761
Nat Neurosci. 2001 Jan;4(1):19-28
11135641
Cell Calcium. 2001 Jan;29(1):1-11
11133351
Acta Neuropathol. 1996;91(6):647-53
8781665
J Pharmacol Exp Ther. 1994 Oct;271(1):507-14
7965750
Free Radic Biol Med. 2002 Jun 1;32(11):1061-70
12031890
J Neurosci. 1997 Jun 1;17(11):4212-22
9151738
J Biol Chem. 2000 Jun 30;275(26):19978-84
10764805
Biochim Biophys Acta. 1996 Jun 7;1316(2):71-7
8672553
Int J Clin Exp Pathol. 2008 Jan 01;1(1):44-56
18784822
Biochem Mol Biol Int. 1995 Jul;36(3):569-77
7549956
Mol Cell Biol. 1997 Jun;17(6):3005-12
9154798
Aging Cell. 2007 Jun;6(3):307-17
17465978
FEBS Lett. 2002 Mar 13;514(2-3):122-8
11943137
Genes Dev. 1999 May 15;13(10):1211-33
10346810
Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):7978-82
1518824
Neurobiol Dis. 2006 Sep;23(3):669-78
16844381
J Neurochem. 1999 Mar;72(3):1019-29
10037473
Free Radic Res. 1996 Apr;24(4):243-59
8731009
Biochim Biophys Acta. 2001 May 31;1536(2-3):85-96
11406343
Life Sci. 1999;64(13):PL165-71
10210280
Int Rev Cytol. 2001;205:149-214
11336391
Circ Res. 1995 Mar;76(3):388-95
7859385
J Chem Neuroanat. 2004 Sep;28(1-2):67-78
15363492
J Neurochem. 1986 Jun;46(6):1820-34
3517233
Trends Microbiol. 2005 Apr;13(4):159-63
15817385
Biochem Soc Trans. 2003 Oct;31(Pt 5):958-9
14505458
Neuron. 1998 Jul;21(1):13-26
9697848