Abstract
Alzheimer's disease (AD) is a very common cause of dementia in the elderly. It is characterized by progressive amnesia and accretions of neurofibrillary tangles (NFTs) of neurons and senile plaques in the neuropil. After aging, the inheritance of the apolipoprotein E (ApoE) epsilon 4 (ε4) allele is the greatest risk factor for late-onset AD. The ApoE protein is the translated product of the ApoE gene. This protein undergoes proteolysis, and the resulting fragments colocalize with neurofibrillary tangles and amyloid plaques, and for that matter may be involved in AD onset and/or progression. Previous studies have reported the pathogenic potential of various ApoE fragments in AD pathophysiology. However, the pathways activated by the fragments are not fully understood. In this review, ApoE fragments obtained from post-mortem brains and body fluids, cerebrospinal fluid (CSF) and plasma, are discussed. Additionally, current knowledge about the process of fragmentation is summarized. Finally, the mechanisms by which these fragments are involved in AD pathogenesis and pathophysiology are discussed.
Funding source: National Natural Science Foundation of China
Award Identifier / Grant number: 81801278
Funding source: Natural Science Foundation of Hebei Province
Award Identifier / Grant number: H2019206637
Funding source: China Scholarship Council
Award Identifier / Grant number: 201608130015
Funding source: Hebei University Science and technology research project
Award Identifier / Grant number: ZD2019049
Funding source: Hebei Provincial Department of Human Resources and Social Security
Award Identifier / Grant number: C20190509
Acknowledgments
This work was supported by Natural Science Foundation of China (Grant No. 81801278), Natural Science Foundation of Hebei Province (Grant No. H2019206637), China Scholarship Council (Grant No. 201608130015), Hebei University Science and technology research project (Grant No. ZD2019049), Excellent Overseas researcher Program in Hebei Provincial Department of Human Resources and Social Security (Grant No. C20190509).
Conflict of interest statement: Authors declare no competing interests.
References
Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G.M., Cooper, N.R., Eikelenboom, P., Emmerling, M., Fiebich, B.L., et al. (2000). Inflammation and Alzheimer's disease. Neurobiol. Aging 21: 383–421, https://doi.org/10.1016/S0197-4580(00)00124-X.10.1016/S0197-4580(00)00124-XSearch in Google Scholar
Aono, M., Bennett, E.R., Kim, K.S., Lynch, J.R., Myers, J., Pearlstein, R.D., Warner, D.S., and Laskowitz, D.T. (2003). Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures. Neuroscience. 116: 437–445, https://doi.org/10.1016/s0306-4522(02)00709-1.10.1016/S0306-4522(02)00709-1Search in Google Scholar
Baranello, R.J., Bharani, K.L., Padmaraju, V., Chopra, N., Lahiri, D.K., Greig, N.H., Pappolla, M.A.,and Sambamurti, K. (2015). Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer's Disease. Curr. Alzheimer Res. 12: 32–46, https://doi.org/10.2174/1567205012666141218140953.10.2174/1567205012666141218140953Search in Google Scholar PubMed PubMed Central
Bekris, L.M., Yu, C.E., Bird, T.D., and Tsuang, D.W. (2010). Genetics of Alzheimer disease. J. Geriatr. Psychiatry. Neurol. 23: 213–227, https://doi.org/10.1177/0891988710383571.10.1177/0891988710383571Search in Google Scholar PubMed PubMed Central
Bertram, L., McQueen, M.B., Mullin, K., Blacker, D., and Tanzi, R.E. (2007). Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat. Genet. 39: 17–23, https://doi.org/10.1038/ng1934.10.1038/ng1934Search in Google Scholar PubMed
Bien-Ly, N., Andrews-Zwilling, Y., Xu, Q., Bernardo, A., Wang, C., and Huang, Y. (2011). C-terminal-truncated apolipoprotein (apo) E4 inefficiently clears amyloid-beta (Abeta) and acts in concert with Abeta to elicit neuronal and behavioral deficits in mice. Proc. Natl. Acad. Sci. U.S.A. 108: 4236–4241, https://doi.org/10.1073/pnas.1018381108.10.1073/pnas.1018381108Search in Google Scholar PubMed PubMed Central
Brecht, W.J., Harris, F.M., Chang, S., Tesseur, I., Yu, G.Q., Xu, Q., Dee Fish, J., Wyss-Coray, T., Buttini, M., Mucke, L., et al. (2004). Neuron-Specific Apolipoprotein E4 Proteolysis Is Associated with Increased Tau Phosphorylation in Brains of Transgenic Mice. J. Neurosci. 24: 2527–2534, https://doi.org/10.1523/jneurosci.4315-03.2004.10.1523/JNEUROSCI.4315-03.2004Search in Google Scholar PubMed PubMed Central
Brownlee, M. (2001). Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813–820, https://doi.org/10.1038/414813a.10.1038/414813aSearch in Google Scholar PubMed
Brownlee, M. (2005). The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625, https://doi.org/10.2337/diabetes.54.6.1615.10.2337/diabetes.54.6.1615Search in Google Scholar PubMed
Bruno, M.A., Mufson, E.J., Wuu, J., and Cuello, A.C. (2009). Increased matrix metalloproteinase 9 activity in mild cognitive impairment. J. Neuropathol. Exp. Neurol. 68: 1309–1318, https://doi.org/10.1097/nen.0b013e3181c22569.10.1097/NEN.0b013e3181c22569Search in Google Scholar PubMed PubMed Central
Chang, S., ran Ma, T., Miranda, R.D., Balestra, M.E., Mahley, R.W., and Huang, Y. (2005). Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc. Natl. Acad. Sci. U.S.A. 102: 18694–18699, https://doi.org/10.1073/pnas.0508254102.10.1073/pnas.0508254102Search in Google Scholar PubMed PubMed Central
Chen, H.K., Liu, Z., Meyer-Franke, A., Brodbeck, J., Miranda, R.D., McGuire, J.G., Pleiss, M.A., Ji, Z.S., Balestra, M.E., Walker, D.W., et al. (2012). Small molecule structure correctors abolish detrimental effects of apolipoprotein E4 in cultured neurons. J. Biol. Chem. 287: 5253–5266, https://doi.org/10.1074/jbc.m111.276162.10.1074/jbc.M111.276162Search in Google Scholar PubMed PubMed Central
Chen, J., Li, Q., and Wang, J. (2011). Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc. Natl. Acad. Sci. U.S.A 108: 14813–14818, https://doi.org/10.1073/pnas.1106420108.10.1073/pnas.1106420108Search in Google Scholar PubMed PubMed Central
Chetty, P.S., Mayne, L., Lund-Katz, S., Englander, S.W., and Phillips, M.C. (2017). Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry. Proc. Natl. Acad. Sci. U.S.A. 114: 968–973, https://doi.org/10.1073/pnas.1617523114.10.1073/pnas.1617523114Search in Google Scholar PubMed PubMed Central
Cho, H.S., Hyman, B.T., Greenberg, S.M., and Rebeck, G.W. (2001). Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in Abeta aggregation. J. Neuropathol. Exp. Neurol. 60: 342–349, https://doi.org/10.1093/jnen/60.4.342.10.1093/jnen/60.4.342Search in Google Scholar PubMed
Chu, Q., Diedrich, J.K., Vaughan, J.M., Donaldson, C.J., Nunn, M.F., Lee, K.F., and Saghatelian, A. (2016). HtrA1 Proteolysis of ApoE In Vitro Is Allele Selective. J. Am. Chem. Soc. 138: 9473–9478, https://doi.org/10.1021/jacs.6b03463.10.1021/jacs.6b03463Search in Google Scholar PubMed PubMed Central
Clay, M.A., Anantharamaiah, G.M., Mistry, M.J., Balasubramaniam, A., and Harmony, J.A. (1995). Localization of a Domain in Apolipoprotein E with both Cytostatic and Cytotoxic Activity. Biochemistry. 34: 11142–11151, https://doi.org/10.1021/bi00035a020.10.1021/bi00035a020Search in Google Scholar PubMed
Costantini, C., Scrable, H., and Puglielli, L. (2006). An aging pathway controls the TrkA to p75NTR receptor switch and amyloid β-peptide generation. EMBO J. 25: 1997–2006, https://doi.org/10.1038/sj.emboj.7601062.10.1038/sj.emboj.7601062Search in Google Scholar PubMed PubMed Central
Crutcher, K.A., Clay, M.A., Scott, S.A., Tian, X., Tolar, M., and Harmony, J.A. (1994). Neurite degeneration elicited by apolipoprotein E peptides. Exp. Neurol. 130: 120–126, https://doi.org/10.1006/exnr.1994.1191.10.1006/exnr.1994.1191Search in Google Scholar PubMed
Cruts, M., van Duijn, C.M., Backhovens, H., Van den Broeck, M., Wehnert, A., Serneels, S., Sherrington, R., Hutton, M., Hardy, J., St George-Hyslop, P.H., et al. (1998). Estimation of the Genetic Contribution of Presenilin-1 and -2 Mutations in a Population-Based Study of Presenile Alzheimer Disease. Hum. Mol. Genet. 7: 43–51, https://doi.org/10.1093/hmg/7.1.43.10.1093/hmg/7.1.43Search in Google Scholar PubMed
Dafnis, I., Argyri, L., Sagnou, M., Tzinia, A., Tsilibary, E.C., Stratikos, E., and Chroni, A. (2016). The ability of apolipoprotein E fragments to promote intraneuronal accumulation of amyloid beta peptide 42 is both isoform and size-specific. Sci. Rep. 6: 30654, https://doi.org/10.1038/srep30654.10.1038/srep30654Search in Google Scholar PubMed PubMed Central
Dafnis, I., Raftopoulou, C., Mountaki, C., Megalou, E., Zannis, V.I., and Chroni, A. (2018). ApoE isoforms and carboxyl-terminal-truncated apoE4 forms affect neuronal BACE1 levels and Aβ production independently of their cholesterol efflux capacity. Biochem. J. 475: 1839–1859, https://doi.org/10.1042/bcj20180068.10.1042/BCJ20180068Search in Google Scholar PubMed
Dafnis, I., Stratikos, E., Tzinia, A., Tsilibary, E.C., Zannis, V.I., and Chroni, A. (2010). An apolipoprotein E4 fragment can promote intracellular accumulation of amyloid peptide beta 42. J. Neurochem. 115: 873–884, https://doi.org/10.1111/j.1471-4159.2010.06756.x.10.1111/j.1471-4159.2010.06756.xSearch in Google Scholar PubMed PubMed Central
Dafnis, I., Tzinia, A.K., Tsilibary, E.C., Zannis, V.I., and Chroni, A. (2012). An apolipoprotein E4 fragment affects matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 1 and cytokine levels in brain cell lines. Neuroscience. 210: 21–32, https://doi.org/10.1016/j.neuroscience.2012.03.013.10.1016/j.neuroscience.2012.03.013Search in Google Scholar PubMed PubMed Central
Dong, L.M., and Weisgraber, K.H. (1996). Human Apolipoprotein E4 Domain Interaction. J. Biol. Chem. 271: 19053–19057, https://doi.org/10.1074/jbc.271.32.19053.10.1074/jbc.271.32.19053Search in Google Scholar PubMed
Frieden, C., and Garai, K. (2012). Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 109: 8913–8918, https://doi.org/10.1073/pnas.1207022109.10.1073/pnas.1207022109Search in Google Scholar PubMed PubMed Central
Frieden, C., Wang, H., and Ho, C.M.W. (2017). A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain-domain interactions. Proc. Natl. Acad. Sci. U.S.A. 114: 6292–6297, https://doi.org/10.1073/pnas.1705080114.10.1073/pnas.1705080114Search in Google Scholar PubMed PubMed Central
Gause, J.W., Day, R.J., Caraway, C.A., Poon, W.W., and Rohn, T.T. (2017). Evaluation of Apolipoprotein E Fragmentation as a Biomarker for Alzheimer's Disease. J. Neurol. Neurol. Disord. 3, https://doi.org/10.15744/2454-4981.3.204.10.15744/2454-4981.3.204Search in Google Scholar PubMed PubMed Central
Gay, E.A., Klein, R.C., and Yakel, J.L. (2006). Apolipoprotein E-derived peptides block alpha7 neuronal nicotinic acetylcholine receptors expressed in xenopus oocytes. J. Pharmacol. Exp. Ther. 316: 835–842, https://doi.org/10.1124/jpet.105.095505.10.1124/jpet.105.095505Search in Google Scholar PubMed
Guo, T., Noble, W., and Hanger, D.P. (2017). Roles of tau protein in heh and disease. Acta Neuropathol. 133: 665–704, https://doi.org/10.1007/s00401-017-1707-9.10.1007/s00401-017-1707-9Search in Google Scholar PubMed PubMed Central
Harris-White, M.E. and Frautschy, S.A. (2005). Low density lipoprotein receptor-related proteins (LRPs), Alzheimer's and cognition. CNS Neurol. Disord. Drug Targets. 4: 469–480, https://doi.org/10.2174/156800705774322102.10.2174/156800705774322102Search in Google Scholar PubMed
Harris, F.M., Brecht, W.J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., Fish, J.D., Masliah, E., Hopkins, P.C., Scearce-Levie, K., et al. (2003). Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 100: 10966–10971, https://doi.org/10.1073/pnas.1434398100.10.1073/pnas.1434398100Search in Google Scholar PubMed PubMed Central
Hauser, P.S. and Ryan, R.O. (2013). Impact of apolipoprotein E on Alzheimer's disease. Curr Alzheimer Res. 10: 809–817, https://doi.org/10.2174/15672050113109990156.10.2174/15672050113109990156Search in Google Scholar PubMed PubMed Central
Heinisch, J.J. and Brandt, R. (2016). Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells. Microbial. Cell (Graz, Austria). 3: 135–146, https://doi.org/10.15698/mic2016.04.489.10.15698/mic2016.04.489Search in Google Scholar PubMed PubMed Central
Hernandez-Zimbron, L.F., Luna-Munoz, J., Mena, R., Vazquez-Ramirez, R., Kubli-Garfias, C., Cribbs, D.H., Manoutcharian, K., and Gevorkian, G. (2012). Amyloid-β peptide binds to cytochrome C oxidase subunit 1. PLoS One. 7: e42344, https://doi.org/10.1016/s0891-5849(99)90960-7.10.1371/journal.pone.0042344Search in Google Scholar PubMed PubMed Central
Hoe, H.S., Freeman, J., and Rebeck, G.W. (2006). Apolipoprotein E decreases tau kinases and phospho-tau levels in primary neurons. Mol. Neurodegener. 1: 18, https://doi.org/10.1186/1750-1326-1-18.10.1186/1750-1326-1-18Search in Google Scholar PubMed PubMed Central
Huang, Y., Liu, X.Q., Wyss-Coray, T., Brecht, W.J., Sanan, D.A., and Mahley, R.W. (2001). Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc. Natl. Acad. Sci. U.S.A. 98: 8838–8843, https://doi.org/10.1073/pnas.151254698.10.1073/pnas.151254698Search in Google Scholar PubMed PubMed Central
Huang, Y. and Mahley, R.W. (2014). Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer's diseases. Neurobiol. Dis. 72 Pt A: 3–12, https://doi.org/10.1016/j.nbd.2014.08.025.10.1016/j.nbd.2014.08.025Search in Google Scholar PubMed PubMed Central
Huang, Y.A., Zhou, B., Wernig, M., and Sudhof, T.C. (2017). ApoE2, ApoE3, and ApoE4 Differentially Stimulate APP Transcription and Abeta Secretion. Cell. 168: 427–441, e421, https://doi.org/10.3410/f.727228791.793527976.10.1016/j.cell.2016.12.044Search in Google Scholar PubMed PubMed Central
Hugo, J. and Ganguli, M. (2014). Dementia and cognitive impairment: epidemiology, diagnosis, and treatment. Clin Geriatr Med. 30: 421–442, https://doi.org/10.1016/j.cger.2014.04.001.10.1016/j.cger.2014.04.001Search in Google Scholar PubMed PubMed Central
Huynh, T.V., Davis, A.A., Ulrich, J.D., and Holtzman, D.M. (2017). Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins. J. Lipid Res. 58: 824–836, https://doi.org/10.1194/jlr.r075481.10.1194/jlr.R075481Search in Google Scholar
Jones, P.B., Adams, K.W., Rozkalne, A., Spires-Jones, T.L., Hshieh, T.T., Hashimoto, T., von Armin, C.A., Mielke, M., Bacskai, B.J., and Hyman, B.T. (2011). Apolipoprotein E: Isoform Specific Differences in Tertiary Structure and Interaction with Amyloid-β in Human Alzheimer Brain. PLoS One. 6: e14586, https://doi.org/10.1371/journal.pone.0014586.10.1371/journal.pone.0014586Search in Google Scholar
Klein, R.C. and Yakel, J.L. (2004). Inhibition of nicotinic acetylcholine receptors by apolipoprotein E-derived peptides in rat hippocampal slices. Neuroscience. 127: 563–567, https://doi.org/10.1016/j.neuroscience.2004.05.045.10.1016/j.neuroscience.2004.05.045Search in Google Scholar
Kockx, M., Jessup, W., and Kritharides, L. (2008). Regulation of endogenous apolipoprotein E secretion by macrophages. Arter. Thromb. Vasc. Biol. 28: 1060–1067, https://doi.org/10.1161/atvbaha.108.164350.10.1161/ATVBAHA.108.164350Search in Google Scholar
Kosik, K.S., Joachim, C.L., and Selkoe, D.J. (1987). Microtubule-associated protein tau is a major antigenic component of paired helical filaments in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 1, https://doi.org/10.1097/00002093-198701030-00022.10.1073/pnas.83.11.4044Search in Google Scholar
Kumar, A., Singh, A., and Ekavali (2015). A review on Alzheimer's disease pathophysiology and its management: An update. Pharmacol. Rep. 67: 195–203, https://doi.org/10.1016/j.pharep.2014.09.004.10.1016/j.pharep.2014.09.004Search in Google Scholar
LaDu, M.J., Falduto, M.T., Manelli, A.M., Reardon, C.A., Getz, G.S., and Frail, D.E. (1994). Isoform-specific binding of apolipoprotein E to beta-amyloid. J. Biol. Chem. 269: 23403–23406, https://doi.org/10.1016/s0169-328x(96)00196-9.10.1016/S0021-9258(17)31529-6Search in Google Scholar
Laskowitz, D.T., Thekdi, A.D., Thekdi, S.D., Han, S.K., Myers, J.K., Pizzo, S.V., and Bennett, E.R. (2001). Downregulation of Microglial Activation by Apolipoprotein E and ApoE-Mimetic Peptides. Exp. Neurol. 167: 74–85, https://doi.org/10.1006/exnr.2001.7541.10.1006/exnr.2001.7541Search in Google Scholar PubMed
Li, Y., Liu, L., Barger, S.W., and Griffin, W.S.T. (2003). Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J. Neurosci. 23: 1605–1611, https://doi.org/10.1523/jneurosci.23-05-01605.2003.10.1523/JNEUROSCI.23-05-01605.2003Search in Google Scholar
Liao, F., Yoon, H., and Kim, J. (2017). Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease. Curr. Opin. Lipidol. 28: 60–67, https://doi.org/10.1097/mol.0000000000000383.10.1097/MOL.0000000000000383Search in Google Scholar PubMed PubMed Central
Love, J.E., Day, R.J., Gause, J.W., Brown, R.J., Pu, X., Theis, D.I., Caraway, C.A., Poon, W.W., Rahman, A.A., Morrison, B.E., et al. (2017). Nuclear uptake of an amino-terminal fragment of apolipoprotein E4 promotes cell death and localizes within microglia of the alzheimer's disease brain. Int. J. Physiol. Pathophysiol. Pharmacol. 9: 40–57. PMID: 28533891.Search in Google Scholar
Lynch, J.R., Tang, W., Wang, H., Vitek, M.P., Bennett, E.R., Sullivan, P.M., Warner, D.S., and Laskowitz, D.T. (2003). APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J. Biol. Chem. 278: 48529–48533, https://doi.org/10.1074/jbc.m306923200.10.1074/jbc.M306923200Search in Google Scholar
Mahley, R.W. (2016). Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism. Arter. Thromb. Vasc. Biol. 36: 1305–1315, https://doi.org/10.1161/atvbaha.116.307023.10.1161/ATVBAHA.116.307023Search in Google Scholar
Manelli, A.M., Stine, W.B., Van Eldik, L.J., and LaDu, M.J. (2004). ApoE and Aβ1–42 Interactions: Effects of Isoform and Conformation on Structure and Function. J. Mol. Neurosci. 23: 235–246, https://doi.org/10.1385/jmn:23:3:235.10.1385/JMN:23:3:235Search in Google Scholar
Marques, M.A., Tolar, M., Harmony, J.A., and Crutcher, K.A. (1996). A thrombin cleavage fragment of apolipoprotein E exhibits isoform-specific neurotoxicity. NeuroReport. 7: 2529–2532, https://doi.org/10.1097/00001756-199611040-00025.10.1097/00001756-199611040-00025Search in Google Scholar PubMed
Masters, C.L., Bateman, R., Blennow, K., Rowe, C.C., Sperling, R.A., and Cummings, J.L. (2015). Alzheimer's disease Nat. Rev. Dis. Primers. 1: 15056, https://doi.org/10.4324/9780203330227_chapter_2.10.1016/B978-0-12-811304-2.00003-1Search in Google Scholar
Morrow, J.A., Hatters, D.M., Lu, B., Hochtl, P., Oberg, K.A., Rupp, B., and Weisgraber, K.H. (2002). Apolipoprotein E4 forms a molten globule: A potential basis for its association with disease. J. Biol. Chem. 277: 50380–50385, https://doi.org/10.1074/jbc.m204898200.10.1074/jbc.M204898200Search in Google Scholar PubMed
Morrow, J.A., Segall, M.L., Lund-Katz, S., Phillips, M.C., Knapp, M., Rupp, B., and Weisgraber, K.H. (2000). Differences in Stability among the Human Apolipoprotein E Isoforms Determined by the Amino-Terminal Domain. Biochemistry. 39: 11657–11666, https://doi.org/10.1021/bi000099m.10.1021/bi000099mSearch in Google Scholar PubMed
Mouchard, A., Boutonnet, M.C., Mazzocco, C., Biendon, N., Macrez, N., and Neuro, C.E.B.N.N. (2019). ApoE-fragment/Aβ heteromers in the brain of patients with Alzheimer's disease. Sci. Rep. 9: 3989, https://doi.org/10.1038/s41598-019-40438-4.10.1038/s41598-019-40438-4Search in Google Scholar PubMed PubMed Central
Moulder, K.L., Narita, M., Chang, L.K., Bu, G., and Johnson, E.M., Jr. (1999). Analysis of a novel mechanism of neuronal toxicity produced by an apolipoprotein E-derived peptide. J. Neurochem. 72: 1069–1080, https://doi.org/10.1046/j.1471-4159.1999.0721069.x.10.1046/j.1471-4159.1999.0721069.xSearch in Google Scholar PubMed
Munoz, S.S., Garner, B., and Ooi, L. (2019). Understanding the Role of ApoE Fragments in Alzheimer's Disease. Neurochem. Res. 44: 1297–1305, https://doi.org/10.1007/s11064-018-2629-1.10.1007/s11064-018-2629-1Search in Google Scholar PubMed
Munoz, S.S., Li, H., Ruberu, K., Chu, Q., Saghatelian, A., Ooi, L., and Garner, B. (2018). The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis. J. Biol. Chem. 293: 4071–4084, https://doi.org/10.1074/jbc.ra117.001278.10.1074/jbc.RA117.001278Search in Google Scholar PubMed PubMed Central
Nakamura, T., Watanabe, A., Fujino, T., Hosono, T., and Michikawa, M. (2009). Apolipoprotein E4 (1-272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells. Mol. Neurodegener. 4: 35, https://doi.org/10.1186/1750-1326-4-35.10.1186/1750-1326-4-35Search in Google Scholar PubMed PubMed Central
O'Brien, R.J. and Wong, P.C. (2011). Amyloid precursor protein processing and Alzheimer's disease. Annu. Rev. Neurosci. 34: 185–204, https://doi.org/10.1146/annurev-neuro-061010-113613.10.1146/annurev-neuro-061010-113613Search in Google Scholar PubMed PubMed Central
Raber, J., Huang, Y., and Ashford, J.W. (2004). ApoE genotype accounts for the vast majority of AD risk and AD pathology. Neurobiol. Aging. 25: 641–650, https://doi.org/10.1016/j.neurobiolAging.2003.12.023.10.1016/j.neurobiolaging.2003.12.023Search in Google Scholar PubMed
Raulin, A.C., Kraft, L., Al-Hilaly, Y.K., Xue, W.F., McGeehan, J.E., Atack, J.R., and Serpell, L. (2019). The Molecular Basis for Apolipoprotein E4 as the Major Risk Factor for Late-Onset Alzheimer's Disease. J. Mol. Biol. 431: 2248–2265, https://doi.org/10.1016/j.jmb.2019.04.019.10.1016/j.jmb.2019.04.019Search in Google Scholar PubMed PubMed Central
Readnower, R.D., Sauerbeck, A.D., and Sullivan, P.G. (2011). Mitochondria, Amyloid β, and Alzheimer's Disease. Int. J. Alzheimers Dis. 2011: 104545, https://doi.org/10.4061/2011/104545.10.4061/2011/104545Search in Google Scholar PubMed PubMed Central
Rohn, T.T., Catlin, L.W., Coonse, K.G., and Habig, J.W. (2012). Identification of an amino-terminal fragment of apolipoprotein E4 that localizes to neurofibrillary tangles of the Alzheimer's disease brain. Brain Res. 1475: 106–115, https://doi.org/10.1016/j.brainres.2012.08.003.10.1016/j.brainres.2012.08.003Search in Google Scholar PubMed
Sakono, M. and Zako, T. (2010). Amyloid oligomers: formation and toxicity of Aβ oligomers. FEBS J. 277: 1348–1358, https://doi.org/10.1111/j.1742-4658.2010.07568.x.10.1111/j.1742-4658.2010.07568.xSearch in Google Scholar PubMed
Tamboli, I.Y., Heo, D., and Rebeck, G.W. (2014). Extracellular proteolysis of apolipoprotein e (apoE) by secreted serine neuronal protease. PLoS One. 9: e93120, https://doi.org/10.1371/journal.pone.0093120.10.1371/journal.pone.0093120Search in Google Scholar PubMed PubMed Central
Tolar, M., Keller, J.N., Chan, S., Mattson, M.P., Marques, M.A., and Crutcher, K.A. (1999). Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity. J Neurosci. 19: 7119–7110, https://doi.org/10.1523/jneurosci.19-16-07100.1999.10.1523/JNEUROSCI.19-16-07100.1999Search in Google Scholar
Tolar, M., Marques, M.A., Harmony, J.A.K., and Crutcher, K.A. (1997). Neurotoxicity of the 22 kDa thrombin-cleavage fragment of apolipoprotein E and related synthetic peptides is receptor-mediated. J. Neurosci. 17: 5678–5686, https://doi.org/10.1523/jneurosci.17-15-05678.1997.10.1523/JNEUROSCI.17-15-05678.1997Search in Google Scholar
Varon, D., Loewenstein, D.A., Potter, E., Greig, M.T., Agron, J., Shen, Q., Zhao, W., Celeste Ramirez, M., Santos, I., Barker, W., et al. (2011). Minimal atrophy of the entorhinal cortex and hippocampus: progression of cognitive impairment. Dement Geriatr. Cogn. Disord. 31: 276–283, https://doi.org/10.1159/000324711.10.1159/000324711Search in Google Scholar
Wang, C., Najm, R., Xu, Q., Jeong, D.E., Walker, D., Balestra, M.E., Yoon, S.Y., Yuan, H., Li, G., Miller, Z.A., et al. (2018). Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. Nat. Med. 24: 647–657, https://doi.org/10.1038/s41591-018-0004-z.10.1038/s41591-018-0004-zSearch in Google Scholar
Wang, M. and Turko, I.V. (2013). Mass Spectrometry Quantification Revealed Accumulation of C-Terminal Fragment of Apolipoprotein E in the Alzheimer's Frontal Cortex. PLoS One. 8: e61498, https://doi.org/10.1371/journal.pone.0061498.10.1371/journal.pone.0061498Search in Google Scholar
Wellnitz, S., Friedlein, A., Bonanni, C., Anquez, V., Goepfert, F., Loetscher, H., Adessi, C., and Czech, C. (2005). A 13 kDa carboxy-terminal fragment of ApoE stabilizes Abeta hexamers. J. Neurochem. 94: 1351–1360, https://doi.org/10.1111/j.1471-4159.2005.03295.x.10.1111/j.1471-4159.2005.03295.xSearch in Google Scholar
Wisniewski, T., Lalowski, M., Golabek, A., Frangione, B., and Vogel, T. (1995). Is Alzheimer's disease an apolipoprotein E amyloidosis? Lancet. 345: 956–958, https://doi.org/10.1016/s0140-6736(95)90701-7.10.1016/S0140-6736(95)90701-7Search in Google Scholar
Wolff, M., Zhang-Haagen, B., Decker, C., Barz, B., Schneider, M., Biehl, R., Radulescu, A., Strodel, B., Willbold, D., and Nagel-Steger, L. (2017). Aβ42 pentamers/hexamers are the smallest detectable oligomers in solution. Sci. Rep. 7: 2493, https://doi.org/10.1038/s41598-017-02370-3.10.1038/s41598-017-02370-3Search in Google Scholar PubMed PubMed Central
Youssef, P., Chami, B., Lim, J., Middleton, T., Sutherland, G.T., and Witting, P.K. (2018). Evidence supporting oxidative stress in a moderately affected area of the brain in Alzheimer's disease. Sci. Rep. 8: 11553, https://doi.org/10.1038/s41598-018-29770-3.10.1038/s41598-018-29770-3Search in Google Scholar PubMed PubMed Central
Zhang, Y.W., Thompson, R., Zhang, H., and Xu, H. (2011). APP processing in Alzheimer's disease. Mol. Brain. 4: 3, https://doi.org/10.1007/978-0-387-35135-3_2.10.1186/1756-6606-4-3Search in Google Scholar PubMed PubMed Central
Zhao, J., Davis, M.D., Martens, Y.A., Shinohara, M., Graff-Radford, N.R., Younkin, S.G., Wszolek, Z.K., Kanekiyo, T., and Bu, G. (2017). APOE ε4/ε4 diminishes neurotrophic function of human iPSC-derived astrocytes. Hum. Mol. Genet. 26: 2690–2700, https://doi.org/10.1093/hmg/ddx155.10.1093/hmg/ddx155Search in Google Scholar PubMed PubMed Central
Zhou, W., Scott, S.A., Shelton, S.B., and Crutcher, K.A. (2006). Cathepsin D-mediated proteolysis of apolipoprotein E: Possible role in Alzheimer's disease. Neuroscience. 143: 689–701, https://doi.org/10.1016/j.neuroscience.2006.08.019.10.1016/j.neuroscience.2006.08.019Search in Google Scholar PubMed
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