Brian Bacskai Kevin Foskett Kim Green Kishore Kuchibhotla Ilya Bezprozvanny Grace (Beth) Stutzmann

A Live Webinar Discussion was held on 29 October 2008, with presentations from Ilya Bezprozvanny, Beth Stutzmann, Kevin Foskett, Kim Green, and Brian Bacskai and Kishore Kuchibhotla. This live discussion began with a Webinar featuring a slide talk with audio provided via a telephone line. Following the talk, the audience moved to a chatroom for Q&A and discussion.

View/Listen to Webinar Recording Note: We regret that the sound quality is low for the first 9 minutes of the presention.

View Transcript of Live Discussion — Posted 9 December 2008

Background Text
By Tom Fagan

Calling all confirmed and potential Calcinists. Though the calcium hypothesis of AD has been with us for nearly two decades, it is only within the last few years that the theory has blossomed, mostly through links to the endoplasmic reticulum (ER). Work from Ilya Bezprozvanny’s lab at the University of Texas Southwestern Medical Center, Dallas, suggested that presenilins, best known as a component of the γ-secretase that released amyloid-β, are actually part of the long sought ER calcium leak channel (see ARF related news story). Beth Stutzmann, Rosalind Franklin University, Chicago, Illinois, has a different take on the presenilin-calcium connection. Her work suggests that presenilins aberrantly modulate the ER ryanodine receptor, and that in a mutant presenilin (PS) background, that channel releases more calcium into the cytosol (see ARF related news story).

Very recent data from Kevin Foskett’s lab at the University of Pennsylvania, Philadelphia, showed that PSs interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) calcium release channel, again in the ER, releasing calcium that then leads to enhanced Aβ production (see ARF related news story). And finally, Kim Green at Frank LaFerla’s lab at University of California, Irvine, recently published data linking PSs to the SERCA pump that drives calcium into the ER (see ARF related news story). And if all this presenilin-ER-calcium news isn’t enough to convince you that there is a connection between AD and calcium, recent analysis from Brian Bacskai’s group at Massachusetts General Hospital, Charlestown, has linked Aβ to calcium toxicity in vivo. Kishore Kuchibhotla and colleagues used in vivo imaging to show that cells in the vicinity of Aβ plaques accumulate intracellular calcium to toxic levels, leading to degeneration of dendritic spines (see ARF related news story).

Do these somewhat disparate observations fit into a single calcium hypothesis of AD? Join Alzforum for a Live Webinar Discussion on 29 October, 12:30 p.m., when Bezprozvanny, Stutzmann, Foskett, Green, and Bacskai and Kuchibhotla will give brief presentations to be followed by a group discussion. As always, your comments are welcome.

	Comments on Live Discussion
	Comment by:  Gary Gibson
	Submitted 29 October 2008  |  Permalink	Posted 29 October 2008
	Using the exact techniques that we used in the Ito studies to look at ER calcium in fibroblasts bearing presenilin mutations, we also examined ER calcium in lines bearing the APP670/671 lines. (No presenilin mutation; single APP mutation; Gibson et al., 1997.) In the lines bearing APP mutation we found a decrease in release of ER with bradykinnin rather than the increase observed in the PS1 lines. Is the role of ER different in cells with single APP mutations? References: Gibson GE, Vestling M, Zhang H, Szolosi S, Alkon D, Lannfelt L, Gandy S, Cowburn RF. Abnormalities in Alzheimer's disease fibroblasts bearing the APP670/671 mutation. Neurobiol Aging. 1997 Nov-Dec;18(6):573-80. Abstract View all comments by Gary Gibson
	Comment by:  Alvin Lyckman
	Submitted 28 October 2008  |  Permalink	Posted 29 October 2008
	Our Ca-sensitive microelectrode measurements show that resting Ca is significantly elevated in adult cultured neurons that express APPswe/β-amyloid in vivo as compared to those from non-transgenic control mice. The elevation appears to be due mainly to excessive influx (through the plasmalemma). In these neurons, ryanodine receptor blockade does not lower internal Ca, but IP3R blockade does (see Lopez et al., 2008). References: Lopez JR, Lyckman A, Oddo S, Laferla FM, Querfurth HW, Shtifman A. Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice. J Neurochem. April, 2008;105(1):262-71. Epub Nov 16, 2007. Abstract View all comments by Alvin Lyckman
	Comment by:  Gregory J Brewer
	Submitted 28 October 2008  |  Permalink	Posted 29 October 2008
	We also have evidence that calcium dynamics are dysregulated in neurons from two-year-old rats (Brewer et al., 2006), so the calcium hypothesis of AD may intersect with the aging in non-familial AD as well. References: Brewer GJ, Reichensperger JD, Brinton RD. Prevention of age-related dysregulation of calcium dynamics by estrogen in neurons. Neurobiol Aging. 2006 Feb;27(2):306-17. Abstract View all comments by Gregory J Brewer
	Comment by:  Massimo Stefani
	Submitted 27 October 2008  |  Permalink	Posted 29 October 2008
	Several recently appeared papers on the AD-Ca2+ relation have undoubtedly shown that the issue has come to ripeness. The data showing a significant increase of free Ca2+ inside neurons close to amyloid plaques, coupled with neuronal degeneration and functional impairment, provide a convincing milestone around which previous research can be coagulated and new research can start to give further knowledge on related issues. The generic cytotoxic effects of prefibrillar amyloids, and in particular the toxicity of Aβ diffusible ligands, and the role of membrane cholesterol in modulating such toxicity may thus gain new significance. Actually, there is increasing support for the scenario whereby Aβ diffusible ligands exert their cytotoxicity in surrounding neurons by affecting cell membrane permeability to free Ca2+ in a cholesterol-dependent way with subsequent Ca2+ ingress into the mitochondria, triggering off oxidative stress and activation of the apoptotic pathways. The scenario accommodates many recently reported data suggesting that Aβ oligomers would increase Ca2+ by affecting...  Read more Several recently appeared papers on the AD-Ca2+ relation have undoubtedly shown that the issue has come to ripeness. The data showing a significant increase of free Ca2+ inside neurons close to amyloid plaques, coupled with neuronal degeneration and functional impairment, provide a convincing milestone around which previous research can be coagulated and new research can start to give further knowledge on related issues. The generic cytotoxic effects of prefibrillar amyloids, and in particular the toxicity of Aβ diffusible ligands, and the role of membrane cholesterol in modulating such toxicity may thus gain new significance. Actually, there is increasing support for the scenario whereby Aβ diffusible ligands exert their cytotoxicity in surrounding neurons by affecting cell membrane permeability to free Ca2+ in a cholesterol-dependent way with subsequent Ca2+ ingress into the mitochondria, triggering off oxidative stress and activation of the apoptotic pathways. The scenario accommodates many recently reported data suggesting that Aβ oligomers would increase Ca2+ by affecting the function of specific Ca2+ channels either in the plasma membrane (as shown by the recently published data on the NMDA and AMPA receptors) and/or by disrupting non-specifically membrane architecture. Both effects, together with APP processing, seem to be modulated by the content of membrane cholesterol as shown by many data, including those focused on the protective role of Seladin-1 against cell damage by soluble Aβ (and other protein) aggregates. Of course, AD is a multifactorial disease even at the molecular and cell biology levels, and other effects must be taken into account including those resulting from glia activation by the plaques. References: Kuchibhotla KV, Goldman ST, Lattarulo CR, Wu HY, Hyman BT, Bacskai BJ. Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. Neuron. 2008 Jul 31;59(2):214-25. Abstract Kelly BL, Ferreira A. beta-Amyloid-induced dynamin 1 degradation is mediated by N-methyl-D-aspartate receptors in hippocampal neurons. J Biol Chem. 2006 Sep 22;281(38):28079-89. Abstract De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL. Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem. 2007 Apr 13;282(15):11590-601. Abstract Pellistri F, Bucciantini M, Relini A, Nosi D, Gliozzi A, Robello M, Stefani M. Nonspecific interaction of prefibrillar amyloid aggregates with glutamatergic receptors results in Ca2+ increase in primary neuronal cells. J Biol Chem. 2008 Oct 31;283(44):29950-60. Abstract Crameri A, Biondi E, Kuehnle K, Lütjohann D, Thelen KM, Perga S, Dotti CG, Nitsch RM, Ledesma MD, Mohajeri MH. The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Abeta generation in vivo. EMBO J. 2006 Jan 25;25(2):432-43. Abstract Cecchi C, Rosati F, Pensalfini A, Formigli L, Nosi D, Liguri G, Dichiara F, Morello M, Danza G, Pieraccini G, Peri A, Serio M, Stefani M. SELADIN-1/DHCR24 PROTECTS NEUROBLASTOMA CELLS AGAINST Abeta TOXICITY BY INCREASING MEMBRANE CHOLESTEROL CONTENT. J Cell Mol Med. 2008 Jan 11; Abstract View all comments by Massimo Stefani
	Comment by:  Alvin Lyckman
	Submitted 16 December 2008  |  Permalink	Posted 18 December 2008
	The best time to attack the dementia of AD is before it begins. Our data concerning abnormal elevation of resting calcium stand in strong distinction to other kinds of neuronal calcium measurements in two critical regards: 1) the mice from which the neurons were taken were young adults (~one year), and 2) in the transgenic strains we used, there are no extracellular amyloid deposits at the ages examined. Thus, these data (Lopez et al., 2008) strongly suggest that either very low levels of extracellular amyloid and/or intracellular amyloid are responsible for elevating resting calcium in neurons of young mice. Modest but significant elevation of intracellular calcium in neurons has profound implications for neuronal function, synaptic plasticity, and pathogenesis. These data suggest that resting calcium may be a critical physiological index of early pathogenesis. This may be significant for treatment development for MCI and for presymptomatic and very early stages of AD dementia. References: Lopez JR, Lyckman A, Oddo S, Laferla FM, Querfurth HW, Shtifman A. Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice. J Neurochem. April, 2008;105(1):262-71. Abstract View all comments by Alvin Lyckman

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