Truncated and modified amyloid-beta species

Markus P Kummer; Michael T Heneka

doi:10.1186/alzrt258

journal article Open Access May 26, 2014

Truncated and modified amyloid-beta species

Markus P Kummer Michael T Heneka

Alzheimer's Research & Therapy Vol. 6 No. 3 · Springer Science and Business Media LLC

View at Publisher Save 10.1186/alzrt258

Abstract

AbstractAlzheimer’s disease pathology is closely connected to the processing of the amyloid precursor protein (APP) resulting in the formation of a variety of amyloid-beta (Aβ) peptides. They are found as insoluble aggregates in senile plaques, the histopathological hallmark of the disease. These peptides are also found in soluble, mostly monomeric and dimeric, forms in the interstitial and cerebrospinal fluid. Due to the combination of several enzymatic activities during APP processing, Aβ peptides exist in multiple isoforms possessing different N-termini and C-termini. These peptides include, to a certain extent, part of the juxtamembrane and transmembrane domain of APP. Besides differences in size, post-translational modifications of Aβ – including oxidation, phosphorylation, nitration, racemization, isomerization, pyroglutamylation, and glycosylation – generate a plethora of peptides with different physiological and pathological properties that may modulate disease progression.

Topics

No keywords indexed for this article. Browse by subject →

References

93

[1]

Querfurth HW, LaFerla FM: Alzheimer’s disease. N Engl J Med. 2010, 362: 329-344. 10.1056/NEJMra0909142. 10.1056/nejmra0909142

[2]

Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease

Kwasi G. Mawuenyega, Wendy Sigurdson, Vitaliy Ovod et al.

Science 2010 10.1126/science.1197623

[3]

Heneka MT, O’Banion MK, Terwel D, Kummer MP: Neuroinflammatory processes in Alzheimer’s disease. J Neural Transm Vienna Austria 1996. 2010, 117: 919-947.

[4]

Thinakaran G, Koo EH: Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008, 283: 29615-29619. 10.1074/jbc.R800019200. 10.1074/jbc.r800019200

[5]

Kuhn P-H, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF: ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 2010, 29: 3020-3032. 10.1038/emboj.2010.167. 10.1038/emboj.2010.167

[6]

β-Secretase Cleavage of Alzheimer's Amyloid Precursor Protein by the Transmembrane Aspartic Protease BACE

Robert Vassar, Brian D. Bennett, Safura Babu-Khan et al.

Science 1999 10.1126/science.286.5440.735

[7]

Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids

Peter Seubert, Carmen Vigo-Pelfrey, Fred Esch et al.

Nature 1992 10.1038/359325a0

[8]

Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C: Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003, 5: 486-488. 10.1038/ncb960. 10.1038/ncb960

[9]

Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y: γ-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci Off J Soc Neurosci. 2009, 29: 13042-13052. 10.1523/JNEUROSCI.2362-09.2009. 10.1523/jneurosci.2362-09.2009

[10]

Qi-Takahara Y, Morishima-Kawashima M, Tanimura Y, Dolios G, Hirotani N, Horikoshi Y, Kametani F, Maeda M, Saido TC, Wang R, Ihara Y: Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase. J Neurosci Off J Soc Neurosci. 2005, 25: 436-445. 10.1523/JNEUROSCI.1575-04.2005. 10.1523/jneurosci.1575-04.2005

[11]

Bibl M, Gallus M, Welge V, Lehmann S, Sparbier K, Esselmann H, Wiltfang J: Characterization of cerebrospinal fluid aminoterminally truncated and oxidized amyloid-β peptides. Proteomics Clin Appl. 2012, 6: 163-169. 10.1002/prca.201100082. 10.1002/prca.201100082

[12]

Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide

Christian Haass, Dennis J. Selkoe

Nature Reviews Molecular Cell Biology 2007 10.1038/nrm2101

[13]

Beher D, Wrigley JDJ, Owens AP, Shearman MS: Generation of C-terminally truncated amyloid-β peptides is dependent on γ-secretase activity. J Neurochem. 2002, 82: 563-575. 10.1046/j.1471-4159.2002.00985.x. 10.1046/j.1471-4159.2002.00985.x

[14]

Portelius E, Price E, Brinkmalm G, Stiteler M, Olsson M, Persson R, Westman-Brinkmalm A, Zetterberg H, Simon AJ, Blennow K: A novel pathway for amyloid precursor protein processing. Neurobiol Aging. 2011, 32: 1090-1098. 10.1016/j.neurobiolaging.2009.06.002. 10.1016/j.neurobiolaging.2009.06.002

[15]

Haass C, Hung AY, Schlossmacher MG, Teplow DB, Selkoe DJ: β-Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms. J Biol Chem. 1993, 268: 3021-3024. 10.1016/s0021-9258(18)53650-4

[16]

Portelius E, Van Broeck B, Andreasson U, Gustavsson MK, Mercken M, Zetterberg H, Borghys H, Blennow K: Acute effect on the Aβ isoform pattern in CSF in response to γ-secretase modulator and inhibitor treatment in dogs. J Alzheimers Dis. 2010, 21: 1005-1012. 10.3233/jad-2010-100573

[17]

Portelius E, Dean RA, Gustavsson MK, Andreasson U, Zetterberg H, Siemers E, Blennow K: A novel Aβ isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease. Alzheimers Res Ther. 2010, 2: 7-10.1186/alzrt30. 10.1186/alzrt30

[18]

Jäger S, Leuchtenberger S, Martin A, Czirr E, Wesselowski J, Dieckmann M, Waldron E, Korth C, Koo EH, Heneka M, Weggen S, Pietrzik CU: Alpha-secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation. J Neurochem. 2009, 111: 1369-1382. 10.1111/j.1471-4159.2009.06420.x. 10.1111/j.1471-4159.2009.06420.x

[19]

Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frébourg T, Checler F: Unusual phenotypic alteration of beta amyloid precursor protein (βAPP) maturation by a new Val-715 → Met βAPP-770 mutation responsible for probable early-onset Alzheimer’s disease. Proc Natl Acad Sci USA. 1999, 96: 4119-4124. 10.1073/pnas.96.7.4119. 10.1073/pnas.96.7.4119

[20]

Schieb H, Kratzin H, Jahn O, Möbius W, Rabe S, Staufenbiel M, Wiltfang J, Klafki HW: Beta-amyloid peptide variants in brains and cerebrospinal fluid from amyloid precursor protein (APP) transgenic mice: comparison with human Alzheimer amyloid. J Biol Chem. 2011, 286: 33747-33758. 10.1074/jbc.M111.246561. 10.1074/jbc.m111.246561

[21]

Sergeant N, Bombois S, Ghestem A, Drobecq H, Kostanjevecki V, Missiaen C, Wattez A, David J-P, Vanmechelen E, Sergheraert C, Delacourte A: Truncated beta-amyloid peptide species in pre-clinical Alzheimer’s disease as new targets for the vaccination approach. J Neurochem. 2003, 85: 1581-1591. 10.1046/j.1471-4159.2003.01818.x. 10.1046/j.1471-4159.2003.01818.x

[22]

Kalback W, Watson MD, Kokjohn TA, Kuo Y-M, Weiss N, Luehrs DC, Lopez J, Brune D, Sisodia SS, Staufenbiel M, Emmerling M, Roher AE: APP transgenic mice Tg2576 accumulate Aβ peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer’s disease senile plaques. Biochemistry (Mosc). 2002, 41: 922-928. 10.1021/bi015685+. 10.1021/bi015685+

[23]

Pike CJ, Overman MJ, Cotman CW: Amino-terminal deletions enhance aggregation of β-amyloid peptides in vitro. J Biol Chem. 1995, 270: 23895-23898. 10.1074/jbc.270.41.23895. 10.1074/jbc.270.41.23895

[24]

Wang DS, Dickson DW, Malter JS: β-Amyloid degradation and Alzheimer’s disease. J Biomed Biotechnol. 2006, 2006: 58406- 10.1155/jbb/2006/58406

[25]

Wiltfang J, Esselmann H, Cupers P, Neumann M, Kretzschmar H, Beyermann M, Schleuder D, Jahn H, Rüther E, Kornhuber J, Annaert W, De Strooper B, Saftig P: Elevation of beta-amyloid peptide 2–42 in sporadic and familial Alzheimer’s disease and its generation in PS1 knockout cells. J Biol Chem. 2001, 276: 42645-42657. 10.1074/jbc.M102790200. 10.1074/jbc.m102790200

[26]

Arai T, Akiyama H, Ikeda K, Kondo H, Mori H: Immunohistochemical localization of amyloid beta-protein with amino-terminal aspartate in the cerebral cortex of patients with Alzheimer’s disease. Brain Res. 1999, 823: 202-206. 10.1016/S0006-8993(98)01366-3. 10.1016/s0006-8993(98)01366-3

[27]

Bibl M, Gallus M, Welge V, Esselmann H, Wolf S, Rüther E, Wiltfang J: Cerebrospinal fluid amyloid-β 2–42 is decreased in Alzheimer’s, but not in frontotemporal dementia. J Neural Transm Vienna Austria 1996. 2012, 119: 805-813.

[28]

Bien J, Jefferson T, Causević M, Jumpertz T, Munter L, Multhaup G, Weggen S, Becker-Pauly C, Pietrzik CU: The metalloprotease meprin β generates amino terminal-truncated amyloid β peptide species. J Biol Chem. 2012, 287: 33304-33313. 10.1074/jbc.M112.395608. 10.1074/jbc.m112.395608

[29]

Wittnam JL, Portelius E, Zetterberg H, Gustavsson MK, Schilling S, Koch B, Demuth H-U, Blennow K, Wirths O, Bayer TA: Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease. J Biol Chem. 2012, 287: 8154-8162. 10.1074/jbc.M111.308601. 10.1074/jbc.m111.308601

[30]

Casas C, Sergeant N, Itier J-M, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T, Drobecq H, Clark A, Bonici B, Delacourte A, Benavides J, Schmitz C, Tremp G, Bayer TA, Benoit P, Pradier L: Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Aβ42 accumulation in a novel Alzheimer transgenic model. Am J Pathol. 2004, 165: 1289-1300. 10.1016/S0002-9440(10)63388-3. 10.1016/s0002-9440(10)63388-3

[31]

Güntert A, Döbeli H, Bohrmann B: High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain. Neuroscience. 2006, 143: 461-475. 10.1016/j.neuroscience.2006.08.027. 10.1016/j.neuroscience.2006.08.027

[32]

Drew SC, Masters CL, Barnham KJ: Alanine-2 carbonyl is an oxygen ligand in Cu2+ coordination of Alzheimer’s disease amyloid-beta peptide – relevance to N-terminally truncated forms. J Am Chem Soc. 2009, 131: 8760-8761. 10.1021/ja903669a. 10.1021/ja903669a

[33]

Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA. 1985, 82: 4245-4249. 10.1073/pnas.82.12.4245. 10.1073/pnas.82.12.4245

[34]

Lewis H, Beher D, Cookson N, Oakley A, Piggott M, Morris CM, Jaros E, Perry R, Ince P, Kenny RA, Ballard CG, Shearman MS, Kalaria RN: Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia. Neuropathol Appl Neurobiol. 2006, 32: 103-118. 10.1111/j.1365-2990.2006.00696.x. 10.1111/j.1365-2990.2006.00696.x

[35]

Bouter Y, Dietrich K, Wittnam JL, Rezaei-Ghaleh N, Pillot T, Papot-Couturier S, Lefebvre T, Sprenger F, Wirths O, Zweckstetter M, Bayer TA: N-truncated amyloid β (Aβ) 4–42 forms stable aggregates and induces acute and long-lasting behavioral deficits. Acta Neuropathol (Berl). 2013, 126: 189-205. 10.1007/s00401-013-1129-2. 10.1007/s00401-013-1129-2

[36]

Takeda K, Araki W, Akiyama H, Tabira T: Amino-truncated amyloid beta-peptide (Aβ5-40/42) produced from caspase-cleaved amyloid precursor protein is deposited in Alzheimer’s disease brain. FASEB J Off Publ Fed Am Soc Exp Biol. 2004, 18: 1755-1757.

[37]

Murayama KS, Kametani F, Tabira T, Araki W: A novel monoclonal antibody specific for the amino-truncated beta-amyloid Aβ5–40/42 produced from caspase-cleaved amyloid precursor protein. J Neurosci Methods. 2007, 161: 244-249. 10.1016/j.jneumeth.2006.11.010. 10.1016/j.jneumeth.2006.11.010

[38]

Portelius E, Olsson M, Brinkmalm G, Rüetschi U, Mattsson N, Andreasson U, Gobom J, Brinkmalm A, Hölttä M, Blennow K, Zetterberg H: Mass spectrometric characterization of amyloid-β species in the 7PA2 cell model of Alzheimer’s disease. J Alzheimers Dis. 2013, 33: 85-93. 10.3233/jad-2012-120994

[39]

Mattsson N, Rajendran L, Zetterberg H, Gustavsson M, Andreasson U, Olsson M, Brinkmalm G, Lundkvist J, Jacobson LH, Perrot L, Neumann U, Borghys H, Mercken M, Dhuyvetter D, Jeppsson F, Blennow K, Portelius E: BACE1 inhibition induces a specific cerebrospinal fluid β-amyloid pattern that identifies drug effects in the central nervous system. PloS One. 2012, 7: e31084-10.1371/journal.pone.0031084. 10.1371/journal.pone.0031084

[40]

Hu J, Igarashi A, Kamata M, Nakagawa H: Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (Aβ); retards Aβ aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem. 2001, 276: 47863-47868. 10.1074/jbc.m104068200

[41]

Näslund J, Schierhorn A, Hellman U, Lannfelt L, Roses AD, Tjernberg LO, Silberring J, Gandy SE, Winblad B, Greengard P: Relative abundance of Alzheimer Aβ amyloid peptide variants in Alzheimer disease and normal aging. Proc Natl Acad Sci USA. 1994, 91: 8378-8382. 10.1073/pnas.91.18.8378. 10.1073/pnas.91.18.8378

[42]

Hensley K, Aksenova M, Carney JM, Harris M, Butterfield DA: Amyloid beta-peptide spin trapping. I: peptide enzyme toxicity is related to free radical spin trap reactivity. Neuroreport. 1995, 6: 489-492. 10.1097/00001756-199502000-00021. 10.1097/00001756-199502000-00021

[43]

Palmblad M, Westlind-Danielsson A, Bergquist J: Oxidation of methionine 35 attenuates formation of amyloid beta-peptide 1–40 oligomers. J Biol Chem. 2002, 277: 19506-19510. 10.1074/jbc.M112218200. 10.1074/jbc.m112218200

[44]

Hou L, Kang I, Marchant RE, Zagorski MG: Methionine 35 oxidation reduces fibril assembly of the amyloid Aβ-(1–42) peptide of Alzheimer’s disease. J Biol Chem. 2002, 277: 40173-40176. 10.1074/jbc.C200338200. 10.1074/jbc.c200338200

[45]

Barnham KJ, Ciccotosto GD, Tickler AK, Ali FE, Smith DG, Williamson NA, Lam Y-H, Carrington D, Tew D, Kocak G, Volitakis I, Separovic F, Barrow CJ, Wade JD, Masters CL, Cherny RA, Curtain CC, Bush AI, Cappai R: Neurotoxic, redox-competent Alzheimer’s beta-amyloid is released from lipid membrane by methionine oxidation. J Biol Chem. 2003, 278: 42959-42965. 10.1074/jbc.M305494200. 10.1074/jbc.m305494200

[46]

Milton NG: Phosphorylation of amyloid-beta at the serine 26 residue by human cdc2 kinase. Neuroreport. 2001, 12: 3839-3844. 10.1097/00001756-200112040-00047. 10.1097/00001756-200112040-00047

[47]

Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M, Mc Donald JM, Wüllner U, Glebov K, Heneka MT, Walsh DM, Zweckstetter M, Walter J: Extracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer’s disease. EMBO J. 2011, 30: 2255-2265. 10.1038/emboj.2011.138. 10.1038/emboj.2011.138

[48]

Kumar S, Wirths O, Theil S, Gerth J, Bayer TA, Walter J: Early intraneuronal accumulation and increased aggregation of phosphorylated Aβ in a mouse model of Alzheimer’s disease. Acta Neuropathol (Berl). 2013, 125: 699-709. 10.1007/s00401-013-1107-8. 10.1007/s00401-013-1107-8

[49]

Kumar S, Singh S, Hinze D, Josten M, Sahl H-G, Siepmann M, Walter J: Phosphorylation of amyloid-β peptide at serine 8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes. J Biol Chem. 2012, 287: 8641-8651. 10.1074/jbc.M111.279133. 10.1074/jbc.m111.279133

[50]

Radi R, Cassina A, Hodara R, Quijano C, Castro L: Peroxynitrite reactions and formation in mitochondria. Free Radic Biol Med. 2002, 33: 1451-1464. 10.1016/S0891-5849(02)01111-5. 10.1016/s0891-5849(02)01111-5

Showing 50 of 93 references

Cited By

285

Steroidogenic acute regulatory protein mediated variations of gender-specific sex neurosteroids in Alzheimer’s disease: Relevance to hormonal and neuronal imbalance

Pulak R. Manna, Shengping Yang · 2025

Neuroscience & Biobehavioral Re...

Amyloid Beta in Aging and Alzheimer’s Disease

Ujala Sehar, Priyanka Rawat · 2022

International Journal of Molecular...

Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases

Urmi Sengupta, Rakez Kayed · 2022

Progress in Neurobiology

From Stroke to Dementia: a Comprehensive Review Exposing Tight Interactions Between Stroke and Amyloid-β Formation

Romain Goulay, Luis Mena Romo · 2019

Translational Stroke Research

Amyloid β Modification: A Key to the Sporadic Alzheimer's Disease?

Evgeny P. Barykin, Vladimir A. Mitkevich · 2017

Frontiers in Genetics

TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

Yaming Wang, Tyler K. Ulland · 2016

Journal of Experimental Medicine

Truncated Amyloid-β(11–40/42) from Alzheimer Disease Binds Cu2+ with a Femtomolar Affinity and Influences Fiber Assembly

Joseph D. Barritt, John H. Viles · 2015

Journal of Biological Chemistry

Metrics

285

Citations

93

References

Details

Published: May 26, 2014
Vol/Issue: 6(3)
License: View

Authors

Cite This Article

Markus P Kummer, Michael T Heneka (2014). Truncated and modified amyloid-beta species. Alzheimer's Research & Therapy, 6(3). https://doi.org/10.1186/alzrt258

Truncated and modified amyloid-beta species

You May Also Like