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The ion channel hypothesis of Alzheimer’s disease (AD), also known as the channel hypothesis or the amyloid beta ion channel hypothesis, is a more recent variant of the amyloid hypothesis of AD, which identifies amyloid beta (Aβ) as the underlying cause of neurotoxicity seen in AD.^[1] While the traditional formulation of the amyloid hypothesis pinpoints insoluble, fibrillar aggregates of Aβ as the basis of disruption of calcium ion homeostasis and subsequent apoptosis in AD,^[1]^[2] the ion channel hypothesis in 1993 introduced the possibility of an ion-channel-forming oligomer of soluble, non-fibrillar Aβ as the cytotoxic species allowing unregulated calcium influx into neurons in AD.^[3]

The ion channel hypothesis is broadly supported as an explanation for the calcium ion influx that disrupts calcium ion homeostasis and induces apoptosis in neurons. Because the extracellular deposition of Aβ fibrils in senile plaques is not sufficient to predict risk or onset of AD, and clinical trials of drugs that target the Aβ fibrillization process have largely failed, the ion channel hypothesis provides novel molecular targets for continued development of AD therapies and for better understanding of the mechanism underlying onset and progression of AD.^[4]

History

The ion channel hypothesis was first proposed by Arispe and colleagues in 1993 upon discovery that Aβ could form unregulated cation-selective ion channels when incorporated into planar lipid bilayers.^[3] Further research showed that a particular fragment of Aβ, Aβ (25-35), spontaneously inserts into planar lipid bilayers to form weakly selective ion channels^[5] and that membrane insertion occurs non-specifically, irreversibly, and with a broad range of oligomer conformations.^[6] Though more recent studies have found that Aβ channels can be blocked by small molecules,^[7] the broad variety of Aβ ion channel conformations and chemistries make it difficult to design a channel blocker specific to Aβ without compromising other ion channels in the cell membrane.^[4]

Aβ ion channel conformation

The Aβ monomer generally assumes an α-helical formation in aqueous solution,^[8] but can reversibly transition between α-helix and β-sheet structures at varying polarities.^[9] Atomic force microscopy captured images of Aβ channel structures that facilitated calcium uptake and subsequent neuritic degeneration.^[10] Molecular dynamics simulations of Aβ in lipid bilayers suggest that Aβ adopts a β-sheet-rich structure within lipid bilayers that gradually evolves to result in a wide variety of relaxed channel conformations.^[11] In particular, data support the organization of Aβ channels in β-barrels, structural formations commonly seen in transmembrane pore-forming toxins including anthrax.^[12]

Mechanism of action

Cytotoxicity caused by ion channel formation is commonly seen in the world of bacteria.^[13] While eukaryotic cells are generally less vulnerable to channel-forming toxins because of their larger volume and stiffer, sterol-containing membranes, several eukaryotic channel-forming toxins have been seen to sidestep these obstacles by forming especially large, stable ion channels or anchoring to sterols in the cell membrane.^[13]^[14]^[15] Neurons are particularly vulnerable to channel-forming toxins because of their reliance on maintenance of strict Na⁺, K⁺, and Ca²⁺ concentration gradients for proper functioning and action potential propagation.^[13] Leakage caused by insertion of an ion channel such as Aβ rapidly alters intracellular ionic concentrations, resulting in energetic stress, failure of signaling, and cell death.^[3]^[13]

^ ^a ^b Ekinci, Fatma J; Linsley, Maria-Dawn; Shea, Thomas B (2000-03-29). "β-Amyloid-induced calcium influx induces apoptosis in culture by oxidative stress rather than tau phosphorylation". Molecular Brain Research. 76 (2): 389–395. doi:10.1016/S0169-328X(00)00025-5.
^ Abramov, Andrey Y.; Canevari, Laura; Duchen, Michael R. (2004-12-06). "Calcium signals induced by amyloid β peptide and their consequences in neurons and astrocytes in culture". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 8th European Symposium on Calcium. 1742 (1–3): 81–87. doi:10.1016/j.bbamcr.2004.09.006.
^ ^a ^b ^c Arispe, N; Rojas, E; Pollard, H B (1993-01-15). "Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum". Proceedings of the National Academy of Sciences of the United States of America. 90 (2): 567–571. ISSN 0027-8424. PMC 45704. PMID 8380642.
^ ^a ^b Jang, Hyunbum; Connelly, Laura; Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh; Kagan, Bruce L.; Nussinov, Ruth (2013-05-22). "Alzheimer's disease: which type of amyloid-preventing drug agents to employ?". Physical Chemistry Chemical Physics. 15 (23). doi:10.1039/c3cp00017f. ISSN 1463-9084. PMC 3663909. PMID 23450150.
^ Mirzabekov, T.; Lin, M. C.; Yuan, W. L.; Marshall, P. J.; Carman, M.; Tomaselli, K.; Lieberburg, I.; Kagan, B. L. (1994-07-29). "Channel Formation in Planar Lipid Bilayers by a Neurotoxic Fragment of the β-Amyloid Peptide". Biochemical and Biophysical Research Communications. 202 (2): 1142–1148. doi:10.1006/bbrc.1994.2047.
^ Jang, Hyunbum; Connelly, Laura; Teran Arce, Fernando; Ramachandran, Srinivasan; Kagan, Bruce L.; Lal, Ratnesh; Nussinov, Ruth (2013-01-08). "Mechanisms for the Insertion of Toxic, Fibril-like β-Amyloid Oligomers into the Membrane". Journal of Chemical Theory and Computation. 9 (1): 822–833. doi:10.1021/ct300916f. ISSN 1549-9618. PMC 3539805. PMID 23316126.
^ Diaz, Juan Carlos; Simakova, Olga; Jacobson, Kenneth A.; Arispe, Nelson; Pollard, Harvey B. (2009-03-03). "Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity". Proceedings of the National Academy of Sciences. 106 (9): 3348–3353. doi:10.1073/pnas.0813355106. ISSN 0027-8424. PMC 2637905. PMID 19204293.
^ Crescenzi, Orlando; Tomaselli, Simona; Guerrini, Remo; Salvadori, Severo; D'Ursi, Anna M.; Temussi, Piero Andrea; Picone, Delia (2002-11-01). "Solution structure of the Alzheimer amyloid β-peptide (1–42) in an apolar microenvironment". European Journal of Biochemistry. 269 (22): 5642–5648. doi:10.1046/j.1432-1033.2002.03271.x. ISSN 1432-1033.
^ Tomaselli, Simona; Esposito, Veronica; Vangone, Paolo; van Nuland, Nico A. J.; Bonvin, Alexandre M. J. J.; Guerrini, Remo; Tancredi, Teodorico; Temussi, Piero A.; Picone, Delia (2006-02-06). "The α-to-β Conformational Transition of Alzheimer's Aβ-(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding". ChemBioChem. 7 (2): 257–267. doi:10.1002/cbic.200500223. ISSN 1439-7633.
^ Lin, Hai; Bhatia, Rajinder; Lal, Ratneshwar (2001-11-01). "Amyloid β protein forms ion channels: implications for Alzheimer's disease pathophysiology". The FASEB Journal. 15 (13): 2433–2444. doi:10.1096/fj.01-0377com. ISSN 0892-6638. PMID 11689468.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Jang, Hyunbum; Zheng, Jie; Nussinov, Ruth (2007-09-15). "Models of beta-amyloid ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process". Biophysical Journal. 93 (6): 1938–1949. doi:10.1529/biophysj.107.110148. ISSN 0006-3495. PMC 1959551. PMID 17526580.
^ Jang, Hyunbum; Arce, Fernando Teran; Ramachandran, Srinivasan; Capone, Ricardo; Lal, Ratnesh; Nussinov, Ruth (2010-12-17). "β-Barrel Topology of Alzheimer's β-Amyloid Ion Channels". Journal of Molecular Biology. 404 (5): 917–934. doi:10.1016/j.jmb.2010.10.025.
^ ^a ^b ^c ^d Azimov, Rustam; Kagan, Bruce L. (2015-01-01). Delcour, Anne H. (ed.). Amyloid Peptide Channels. Springer Series in Biophysics. Springer International Publishing. pp. 343–360. ISBN 9783319201481.
^ Kagan, B. L. (1983-04-21). "Mode of action of yeast killer toxins: channel formation in lipid bilayer membranes". Nature. 302 (5910): 709–711. ISSN 0028-0836. PMID 6300695.
^ Ng, Agatha W. K.; Wasan, Kishor M.; Lopez-Berestein, Gabriel (2003-04-01). "Development of liposomal polyene antibiotics: an historical perspective". Journal of Pharmacy & Pharmaceutical Sciences: A Publication of the Canadian Society for Pharmaceutical Sciences, Société Canadienne Des Sciences Pharmaceutiques. 6 (1): 67–83. ISSN 1482-1826. PMID 12753730.

[:0-1] Ekinci, Fatma J; Linsley, Maria-Dawn; Shea, Thomas B (2000-03-29). "β-Amyloid-induced calcium influx induces apoptosis in culture by oxidative stress rather than tau phosphorylation". Molecular Brain Research. 76 (2): 389–395. doi:10.1016/S0169-328X(00)00025-5.

[2] Abramov, Andrey Y.; Canevari, Laura; Duchen, Michael R. (2004-12-06). "Calcium signals induced by amyloid β peptide and their consequences in neurons and astrocytes in culture". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 8th European Symposium on Calcium. 1742 (1–3): 81–87. doi:10.1016/j.bbamcr.2004.09.006.

[:1-3] Arispe, N; Rojas, E; Pollard, H B (1993-01-15). "Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum". Proceedings of the National Academy of Sciences of the United States of America. 90 (2): 567–571. ISSN 0027-8424. PMC 45704. PMID 8380642.

[:2-4] Jang, Hyunbum; Connelly, Laura; Arce, Fernando Teran; Ramachandran, Srinivasan; Lal, Ratnesh; Kagan, Bruce L.; Nussinov, Ruth (2013-05-22). "Alzheimer's disease: which type of amyloid-preventing drug agents to employ?". Physical Chemistry Chemical Physics. 15 (23). doi:10.1039/c3cp00017f. ISSN 1463-9084. PMC 3663909. PMID 23450150.

[5] Mirzabekov, T.; Lin, M. C.; Yuan, W. L.; Marshall, P. J.; Carman, M.; Tomaselli, K.; Lieberburg, I.; Kagan, B. L. (1994-07-29). "Channel Formation in Planar Lipid Bilayers by a Neurotoxic Fragment of the β-Amyloid Peptide". Biochemical and Biophysical Research Communications. 202 (2): 1142–1148. doi:10.1006/bbrc.1994.2047.

[6] Jang, Hyunbum; Connelly, Laura; Teran Arce, Fernando; Ramachandran, Srinivasan; Kagan, Bruce L.; Lal, Ratnesh; Nussinov, Ruth (2013-01-08). "Mechanisms for the Insertion of Toxic, Fibril-like β-Amyloid Oligomers into the Membrane". Journal of Chemical Theory and Computation. 9 (1): 822–833. doi:10.1021/ct300916f. ISSN 1549-9618. PMC 3539805. PMID 23316126.

[7] Diaz, Juan Carlos; Simakova, Olga; Jacobson, Kenneth A.; Arispe, Nelson; Pollard, Harvey B. (2009-03-03). "Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity". Proceedings of the National Academy of Sciences. 106 (9): 3348–3353. doi:10.1073/pnas.0813355106. ISSN 0027-8424. PMC 2637905. PMID 19204293.

[8] Crescenzi, Orlando; Tomaselli, Simona; Guerrini, Remo; Salvadori, Severo; D'Ursi, Anna M.; Temussi, Piero Andrea; Picone, Delia (2002-11-01). "Solution structure of the Alzheimer amyloid β-peptide (1–42) in an apolar microenvironment". European Journal of Biochemistry. 269 (22): 5642–5648. doi:10.1046/j.1432-1033.2002.03271.x. ISSN 1432-1033.

[9] Tomaselli, Simona; Esposito, Veronica; Vangone, Paolo; van Nuland, Nico A. J.; Bonvin, Alexandre M. J. J.; Guerrini, Remo; Tancredi, Teodorico; Temussi, Piero A.; Picone, Delia (2006-02-06). "The α-to-β Conformational Transition of Alzheimer's Aβ-(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding". ChemBioChem. 7 (2): 257–267. doi:10.1002/cbic.200500223. ISSN 1439-7633.

[10] Lin, Hai; Bhatia, Rajinder; Lal, Ratneshwar (2001-11-01). "Amyloid β protein forms ion channels: implications for Alzheimer's disease pathophysiology". The FASEB Journal. 15 (13): 2433–2444. doi:10.1096/fj.01-0377com. ISSN 0892-6638. PMID 11689468.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[11] Jang, Hyunbum; Zheng, Jie; Nussinov, Ruth (2007-09-15). "Models of beta-amyloid ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process". Biophysical Journal. 93 (6): 1938–1949. doi:10.1529/biophysj.107.110148. ISSN 0006-3495. PMC 1959551. PMID 17526580.

[12] Jang, Hyunbum; Arce, Fernando Teran; Ramachandran, Srinivasan; Capone, Ricardo; Lal, Ratnesh; Nussinov, Ruth (2010-12-17). "β-Barrel Topology of Alzheimer's β-Amyloid Ion Channels". Journal of Molecular Biology. 404 (5): 917–934. doi:10.1016/j.jmb.2010.10.025.

[:3-13] Azimov, Rustam; Kagan, Bruce L. (2015-01-01). Delcour, Anne H. (ed.). Amyloid Peptide Channels. Springer Series in Biophysics. Springer International Publishing. pp. 343–360. ISBN 9783319201481.

[14] Kagan, B. L. (1983-04-21). "Mode of action of yeast killer toxins: channel formation in lipid bilayer membranes". Nature. 302 (5910): 709–711. ISSN 0028-0836. PMID 6300695.

[15] Ng, Agatha W. K.; Wasan, Kishor M.; Lopez-Berestein, Gabriel (2003-04-01). "Development of liposomal polyene antibiotics: an historical perspective". Journal of Pharmacy & Pharmaceutical Sciences: A Publication of the Canadian Society for Pharmaceutical Sciences, Société Canadienne Des Sciences Pharmaceutiques. 6 (1): 67–83. ISSN 1482-1826. PMID 12753730.

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 {{Orphan|date=May 2016}}
-The [[ion channel]] hypothesis of [[Alzheimer’s disease]] (AD), also known as the channel hypothesis or the [[amyloid beta]] ion channel hypothesis, is a more recent variant of the amyloid hypothesis of AD, which identifies [[amyloid beta]] (Aβ) as the underlying cause of [[neurotoxicity]] seen in AD.<ref name=":0">{{Cite journal|last=Ekinci|first=Fatma J|last2=Linsley|first2=Maria-Dawn|last3=Shea|first3=Thomas B|date=2000-03-29|title=β-Amyloid-induced calcium influx induces apoptosis in culture by oxidative stress rather than tau phosphorylation|url=http://www.sciencedirect.com/science/article/pii/S0169328X00000255|journal=Molecular Brain Research|volume=76|issue=2|pages=389–395|doi=10.1016/S0169-328X(00)00025-5}}</ref> While the traditional formulation of the amyloid hypothesis pinpoints insoluble, fibrillar aggregates of Aβ as the basis of disruption of [[calcium]] ion [[homeostasis]] and subsequent [[apoptosis]] in AD,<ref name=":0" /><ref>{{Cite journal|last=Abramov|first=Andrey Y.|last2=Canevari|first2=Laura|last3=Duchen|first3=Michael R.|date=2004-12-06|title=Calcium signals induced by amyloid β peptide and their consequences in neurons and astrocytes in culture|url=http://www.sciencedirect.com/science/article/pii/S0167488904002241|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|series=8th European Symposium on Calcium|volume=1742|issue=1–3|pages=81–87|doi=10.1016/j.bbamcr.2004.09.006}}</ref> the ion channel hypothesis in 1993 introduced the possibility of an ion-channel-forming [[oligomer]] of soluble, non-fibrillar Aβ as the cytotoxic species allowing unregulated calcium influx into neurons in AD.<ref name=":1">{{Cite journal|last=Arispe|first=N|last2=Rojas|first2=E|last3=Pollard|first3=H B|date=1993-01-15|title=Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum.|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC45704/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=90|issue=2|pages=567–571|issn=0027-8424|pmc=45704|pmid=8380642}}</ref>
+The [[ion channel]] hypothesis of [[Alzheimer’s disease]] (AD), also known as the channel hypothesis or the [[amyloid beta]] ion channel hypothesis, is a more recent variant of the [[Alzheimer's disease#Amyloid hypothesis|amyloid hypothesis]] of AD, which identifies [[amyloid beta]] (Aβ) as the underlying cause of [[neurotoxicity]] seen in AD.<ref name=":0">{{Cite journal|last=Ekinci|first=Fatma J|last2=Linsley|first2=Maria-Dawn|last3=Shea|first3=Thomas B|date=2000-03-29|title=β-Amyloid-induced calcium influx induces apoptosis in culture by oxidative stress rather than tau phosphorylation|url=http://www.sciencedirect.com/science/article/pii/S0169328X00000255|journal=Molecular Brain Research|volume=76|issue=2|pages=389–395|doi=10.1016/S0169-328X(00)00025-5}}</ref> While the traditional formulation of the amyloid hypothesis pinpoints insoluble, fibrillar aggregates of Aβ as the basis of disruption of [[calcium]] ion [[homeostasis]] and subsequent [[apoptosis]] in AD,<ref name=":0" /><ref>{{Cite journal|last=Abramov|first=Andrey Y.|last2=Canevari|first2=Laura|last3=Duchen|first3=Michael R.|date=2004-12-06|title=Calcium signals induced by amyloid β peptide and their consequences in neurons and astrocytes in culture|url=http://www.sciencedirect.com/science/article/pii/S0167488904002241|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|series=8th European Symposium on Calcium|volume=1742|issue=1–3|pages=81–87|doi=10.1016/j.bbamcr.2004.09.006}}</ref> the ion channel hypothesis in 1993 introduced the possibility of an ion-channel-forming [[oligomer]] of soluble, non-fibrillar Aβ as the [[Cytotoxicity|cytotoxic]] species allowing unregulated calcium influx into neurons in AD.<ref name=":1">{{Cite journal|last=Arispe|first=N|last2=Rojas|first2=E|last3=Pollard|first3=H B|date=1993-01-15|title=Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum.|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC45704/|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=90|issue=2|pages=567–571|issn=0027-8424|pmc=45704|pmid=8380642}}</ref>
 The ion channel hypothesis is broadly supported as an explanation for the calcium ion influx that disrupts calcium ion homeostasis and induces apoptosis in [[neurons]]. Because the extracellular deposition of Aβ fibrils in [[senile plaques]] is not sufficient to predict risk or onset of AD, and [[clinical trials]] of drugs that target the Aβ fibrillization process have largely failed, the ion channel hypothesis provides novel molecular targets for continued development of [[Alzheimer's disease research|AD therapies]] and for better understanding of the mechanism underlying onset and progression of AD.<ref name=":2">{{Cite journal|last=Jang|first=Hyunbum|last2=Connelly|first2=Laura|last3=Arce|first3=Fernando Teran|last4=Ramachandran|first4=Srinivasan|last5=Lal|first5=Ratnesh|last6=Kagan|first6=Bruce L.|last7=Nussinov|first7=Ruth|date=2013-05-22|title=Alzheimer's disease: which type of amyloid-preventing drug agents to employ?|url=http://doi.org/10.1039/c3cp00017f|journal=Physical Chemistry Chemical Physics|language=en|volume=15|issue=23|doi=10.1039/c3cp00017f|issn=1463-9084|pmc=3663909|pmid=23450150}}</ref>
 == History ==
-The ion channel hypothesis was first proposed by Arispe and colleagues in 1993 upon discovery that Aβ could form unregulated [[cation]]-selective ion channels when incorporated into planar lipid bilayers.<ref name=":1" /> Further research showed that a particular fragment of Aβ, Aβ (25-35), spontaneously inserts into planar lipid bilayers to form weakly selective ion channels<ref>{{Cite journal|last=Mirzabekov|first=T.|last2=Lin|first2=M. C.|last3=Yuan|first3=W. L.|last4=Marshall|first4=P. J.|last5=Carman|first5=M.|last6=Tomaselli|first6=K.|last7=Lieberburg|first7=I.|last8=Kagan|first8=B. L.|date=1994-07-29|title=Channel Formation in Planar Lipid Bilayers by a Neurotoxic Fragment of the β-Amyloid Peptide|url=http://www.sciencedirect.com/science/article/pii/S0006291X8472047X|journal=Biochemical and Biophysical Research Communications|volume=202|issue=2|pages=1142–1148|doi=10.1006/bbrc.1994.2047}}</ref> and that membrane insertion occurs non-specifically, irreversibly, and with a broad range of oligomer conformations.<ref>{{Cite journal|last=Jang|first=Hyunbum|last2=Connelly|first2=Laura|last3=Teran Arce|first3=Fernando|last4=Ramachandran|first4=Srinivasan|last5=Kagan|first5=Bruce L.|last6=Lal|first6=Ratnesh|last7=Nussinov|first7=Ruth|date=2013-01-08|title=Mechanisms for the Insertion of Toxic, Fibril-like β-Amyloid Oligomers into the Membrane|url=http://dx.doi.org/10.1021/ct300916f|journal=Journal of Chemical Theory and Computation|volume=9|issue=1|pages=822–833|doi=10.1021/ct300916f|issn=1549-9618|pmc=3539805|pmid=23316126}}</ref> Though more recent studies have found that Aβ channels can be blocked by small molecules,<ref>{{Cite journal|last=Diaz|first=Juan Carlos|last2=Simakova|first2=Olga|last3=Jacobson|first3=Kenneth A.|last4=Arispe|first4=Nelson|last5=Pollard|first5=Harvey B.|date=2009-03-03|title=Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity|url=http://www.pnas.org/content/106/9/3348|journal=Proceedings of the National Academy of Sciences|language=en|volume=106|issue=9|pages=3348–3353|doi=10.1073/pnas.0813355106|issn=0027-8424|pmc=2637905|pmid=19204293}}</ref> the broad variety of Aβ ion channel conformations and chemistries make it difficult to design a channel blocker specific to Aβ without compromising other ion channels.<ref name=":2" />
+The ion channel hypothesis was first proposed by Arispe and colleagues in 1993 upon discovery that Aβ could form unregulated [[cation]]-selective ion channels when incorporated into planar lipid bilayers.<ref name=":1" /> Further research showed that a particular fragment of Aβ, Aβ (25-35), spontaneously inserts into planar lipid bilayers to form weakly selective ion channels<ref>{{Cite journal|last=Mirzabekov|first=T.|last2=Lin|first2=M. C.|last3=Yuan|first3=W. L.|last4=Marshall|first4=P. J.|last5=Carman|first5=M.|last6=Tomaselli|first6=K.|last7=Lieberburg|first7=I.|last8=Kagan|first8=B. L.|date=1994-07-29|title=Channel Formation in Planar Lipid Bilayers by a Neurotoxic Fragment of the β-Amyloid Peptide|url=http://www.sciencedirect.com/science/article/pii/S0006291X8472047X|journal=Biochemical and Biophysical Research Communications|volume=202|issue=2|pages=1142–1148|doi=10.1006/bbrc.1994.2047}}</ref> and that membrane insertion occurs non-specifically, irreversibly, and with a broad range of oligomer conformations.<ref>{{Cite journal|last=Jang|first=Hyunbum|last2=Connelly|first2=Laura|last3=Teran Arce|first3=Fernando|last4=Ramachandran|first4=Srinivasan|last5=Kagan|first5=Bruce L.|last6=Lal|first6=Ratnesh|last7=Nussinov|first7=Ruth|date=2013-01-08|title=Mechanisms for the Insertion of Toxic, Fibril-like β-Amyloid Oligomers into the Membrane|url=http://dx.doi.org/10.1021/ct300916f|journal=Journal of Chemical Theory and Computation|volume=9|issue=1|pages=822–833|doi=10.1021/ct300916f|issn=1549-9618|pmc=3539805|pmid=23316126}}</ref> Though more recent studies have found that Aβ channels can be blocked by small molecules,<ref>{{Cite journal|last=Diaz|first=Juan Carlos|last2=Simakova|first2=Olga|last3=Jacobson|first3=Kenneth A.|last4=Arispe|first4=Nelson|last5=Pollard|first5=Harvey B.|date=2009-03-03|title=Small molecule blockers of the Alzheimer Aβ calcium channel potently protect neurons from Aβ cytotoxicity|url=http://www.pnas.org/content/106/9/3348|journal=Proceedings of the National Academy of Sciences|language=en|volume=106|issue=9|pages=3348–3353|doi=10.1073/pnas.0813355106|issn=0027-8424|pmc=2637905|pmid=19204293}}</ref> the broad variety of Aβ ion channel conformations and chemistries make it difficult to design a channel blocker specific to Aβ without compromising other ion channels in the cell membrane.<ref name=":2" />
-== Aβ ion channel conformations ==
+== Aβ ion channel conformation ==
-The Aβ monomer generally assumes an α-helical formation in aqueous solution,<ref>{{Cite journal|last=Crescenzi|first=Orlando|last2=Tomaselli|first2=Simona|last3=Guerrini|first3=Remo|last4=Salvadori|first4=Severo|last5=D'Ursi|first5=Anna M.|last6=Temussi|first6=Piero Andrea|last7=Picone|first7=Delia|date=2002-11-01|title=Solution structure of the Alzheimer amyloid β-peptide (1–42) in an apolar microenvironment|url=http://onlinelibrary.wiley.com/doi/10.1046/j.1432-1033.2002.03271.x/abstract|journal=European Journal of Biochemistry|language=en|volume=269|issue=22|pages=5642–5648|doi=10.1046/j.1432-1033.2002.03271.x|issn=1432-1033}}</ref> but can reversibly transition between α-helix and β-sheet structures at varying polarities.<ref>{{Cite journal|last=Tomaselli|first=Simona|last2=Esposito|first2=Veronica|last3=Vangone|first3=Paolo|last4=van Nuland|first4=Nico A. J.|last5=Bonvin|first5=Alexandre M. J. J.|last6=Guerrini|first6=Remo|last7=Tancredi|first7=Teodorico|last8=Temussi|first8=Piero A.|last9=Picone|first9=Delia|date=2006-02-06|title=The α-to-β Conformational Transition of Alzheimer's Aβ-(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding|url=http://onlinelibrary.wiley.com/doi/10.1002/cbic.200500223/abstract|journal=ChemBioChem|language=en|volume=7|issue=2|pages=257–267|doi=10.1002/cbic.200500223|issn=1439-7633}}</ref> Atomic force microscopy was used to capture images of Aβ channel structures that were also shown to facilitate calcium uptake and neuritic degeneration.<ref>{{Cite journal|last=Lin|first=Hai|last2=Bhatia|first2=Rajinder|last3=Lal|first3=Ratneshwar|date=2001-11-01|title=Amyloid β protein forms ion channels: implications for Alzheimer’s disease pathophysiology|url=http://www.fasebj.org/content/15/13/2433|journal=The FASEB Journal|language=en|volume=15|issue=13|pages=2433–2444|doi=10.1096/fj.01-0377com|issn=0892-6638|pmid=11689468}}</ref> Molecular dynamics simulations of Aβ in lipid bilayers suggest that Aβ adopts a β-sheet-rich structure within lipid bilayers that gradually evolves to result in a wide variety of relaxed channel conformations.<ref>{{Cite journal|last=Jang|first=Hyunbum|last2=Zheng|first2=Jie|last3=Nussinov|first3=Ruth|date=2007-09-15|title=Models of beta-amyloid ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process|url=http://www.ncbi.nlm.nih.gov/pubmed/17526580|journal=Biophysical Journal|volume=93|issue=6|pages=1938–1949|doi=10.1529/biophysj.107.110148|issn=0006-3495|pmc=1959551|pmid=17526580}}</ref> In particular, data support the organization of Aβ channels in β-barrels, structural formations commonly seen in transmembrane pore-forming toxins including anthrax.<ref>{{Cite journal|last=Jang|first=Hyunbum|last2=Arce|first2=Fernando Teran|last3=Ramachandran|first3=Srinivasan|last4=Capone|first4=Ricardo|last5=Lal|first5=Ratnesh|last6=Nussinov|first6=Ruth|date=2010-12-17|title=β-Barrel Topology of Alzheimer's β-Amyloid Ion Channels|url=http://www.sciencedirect.com/science/article/pii/S0022283610011332|journal=Journal of Molecular Biology|volume=404|issue=5|pages=917–934|doi=10.1016/j.jmb.2010.10.025}}</ref>
+The Aβ monomer generally assumes an α-helical formation in aqueous solution,<ref>{{Cite journal|last=Crescenzi|first=Orlando|last2=Tomaselli|first2=Simona|last3=Guerrini|first3=Remo|last4=Salvadori|first4=Severo|last5=D'Ursi|first5=Anna M.|last6=Temussi|first6=Piero Andrea|last7=Picone|first7=Delia|date=2002-11-01|title=Solution structure of the Alzheimer amyloid β-peptide (1–42) in an apolar microenvironment|url=http://onlinelibrary.wiley.com/doi/10.1046/j.1432-1033.2002.03271.x/abstract|journal=European Journal of Biochemistry|language=en|volume=269|issue=22|pages=5642–5648|doi=10.1046/j.1432-1033.2002.03271.x|issn=1432-1033}}</ref> but can reversibly transition between α-helix and β-sheet structures at varying polarities.<ref>{{Cite journal|last=Tomaselli|first=Simona|last2=Esposito|first2=Veronica|last3=Vangone|first3=Paolo|last4=van Nuland|first4=Nico A. J.|last5=Bonvin|first5=Alexandre M. J. J.|last6=Guerrini|first6=Remo|last7=Tancredi|first7=Teodorico|last8=Temussi|first8=Piero A.|last9=Picone|first9=Delia|date=2006-02-06|title=The α-to-β Conformational Transition of Alzheimer's Aβ-(1–42) Peptide in Aqueous Media is Reversible: A Step by Step Conformational Analysis Suggests the Location of β Conformation Seeding|url=http://onlinelibrary.wiley.com/doi/10.1002/cbic.200500223/abstract|journal=ChemBioChem|language=en|volume=7|issue=2|pages=257–267|doi=10.1002/cbic.200500223|issn=1439-7633}}</ref> Atomic force microscopy captured images of Aβ channel structures that facilitated calcium uptake and subsequent neuritic degeneration.<ref>{{Cite journal|last=Lin|first=Hai|last2=Bhatia|first2=Rajinder|last3=Lal|first3=Ratneshwar|date=2001-11-01|title=Amyloid β protein forms ion channels: implications for Alzheimer’s disease pathophysiology|url=http://www.fasebj.org/content/15/13/2433|journal=The FASEB Journal|language=en|volume=15|issue=13|pages=2433–2444|doi=10.1096/fj.01-0377com|issn=0892-6638|pmid=11689468}}</ref> Molecular dynamics simulations of Aβ in lipid bilayers suggest that Aβ adopts a β-sheet-rich structure within lipid bilayers that gradually evolves to result in a wide variety of relaxed channel conformations.<ref>{{Cite journal|last=Jang|first=Hyunbum|last2=Zheng|first2=Jie|last3=Nussinov|first3=Ruth|date=2007-09-15|title=Models of beta-amyloid ion channels in the membrane suggest that channel formation in the bilayer is a dynamic process|url=http://www.ncbi.nlm.nih.gov/pubmed/17526580|journal=Biophysical Journal|volume=93|issue=6|pages=1938–1949|doi=10.1529/biophysj.107.110148|issn=0006-3495|pmc=1959551|pmid=17526580}}</ref> In particular, data support the organization of Aβ channels in β-barrels, structural formations commonly seen in transmembrane pore-forming toxins including anthrax.<ref>{{Cite journal|last=Jang|first=Hyunbum|last2=Arce|first2=Fernando Teran|last3=Ramachandran|first3=Srinivasan|last4=Capone|first4=Ricardo|last5=Lal|first5=Ratnesh|last6=Nussinov|first6=Ruth|date=2010-12-17|title=β-Barrel Topology of Alzheimer's β-Amyloid Ion Channels|url=http://www.sciencedirect.com/science/article/pii/S0022283610011332|journal=Journal of Molecular Biology|volume=404|issue=5|pages=917–934|doi=10.1016/j.jmb.2010.10.025}}</ref>
+== Mechanism of action ==
+[[Cytotoxicity]] caused by ion channel formation is commonly seen in the world of bacteria.<ref name=":3">{{Cite book|url=http://link.springer.com/chapter/10.1007/978-3-319-20149-8_14|title=Amyloid Peptide Channels|last=Azimov|first=Rustam|last2=Kagan|first2=Bruce L.|date=2015-01-01|publisher=Springer International Publishing|isbn=9783319201481|editor-last=Delcour|editor-first=Anne H.|series=Springer Series in Biophysics|pages=343–360|language=en}}</ref> While [[Eukaryote|eukaryotic]] cells are generally less vulnerable to channel-forming toxins because of their larger volume and stiffer, [[sterol]]-containing membranes, several eukaryotic channel-forming toxins have been seen to sidestep these obstacles by forming especially large, stable ion channels or anchoring to sterols in the cell membrane.<ref name=":3" /><ref>{{Cite journal|last=Kagan|first=B. L.|date=1983-04-21|title=Mode of action of yeast killer toxins: channel formation in lipid bilayer membranes|url=http://www.ncbi.nlm.nih.gov/pubmed/6300695|journal=Nature|volume=302|issue=5910|pages=709–711|issn=0028-0836|pmid=6300695}}</ref><ref>{{Cite journal|last=Ng|first=Agatha W. K.|last2=Wasan|first2=Kishor M.|last3=Lopez-Berestein|first3=Gabriel|date=2003-04-01|title=Development of liposomal polyene antibiotics: an historical perspective|url=http://www.ncbi.nlm.nih.gov/pubmed/12753730|journal=Journal of Pharmacy & Pharmaceutical Sciences: A Publication of the Canadian Society for Pharmaceutical Sciences, Société Canadienne Des Sciences Pharmaceutiques|volume=6|issue=1|pages=67–83|issn=1482-1826|pmid=12753730}}</ref> Neurons are particularly vulnerable to channel-forming toxins because of their reliance on maintenance of strict [[Sodium|Na<sup>+</sup>]], [[Potassium|K<sup>+</sup>]], and [[Calcium in biology|Ca<sup>2+</sup>]] concentration gradients for proper functioning and [[action potential]] propagation.<ref name=":3" /> Leakage caused by insertion of an ion channel such as Aβ rapidly alters intracellular ionic concentrations, resulting in energetic stress, failure of signaling, and cell death.<ref name=":1" /><ref name=":3" />
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