Abstract
Alzheimer’s disease (AD) is one of the most devastating neurodegenerative diseases. It has been known for decades that the APOE ɛ4 allele is the most significant genetic risk factor for late-onset AD and yet its precise role in the disease remains unclear. The APOE gene encodes apolipoprotein E (apoE), a 35 kDa glycoprotein highly expressed in the brain. There are three different isoforms: apoE3 is the most common allele in the population, whilst apoE2 decreases, and apoE4 increases AD risk. ApoE has numerous functions that affect neuronal and non-neuronal cells, thus how it contributes to disease onset and progression is hotly debated. The apoE4 isoform has been linked to the accumulation of both of the major pathological hallmarks of AD, amyloid plaques containing amyloid β peptides, and neurofibrillary tangles containing hyperphosphorylated tau protein, as well as other hallmarks of the disease, including inflammation and oxidative stress. Numerous studies have shown that apoE undergoes fragmentation in the human brain, and that the fragmentation pattern varies between isoforms. It was previously shown that apoE4 has neurotoxic functions, however recent data has also identified a neuroprotective role for the apoE N-terminal 25 kDa fragment, which is more prevalent in apoE3 individuals. The ability of the apoE 25 kDa fragment to promote neurite outgrowth was recently demonstrated and this suggests there is a potential loss of neuroprotection in apoE4 individuals in addition to the previously described gain of toxic function for specific apoE4 fragments. Here we review the enzymes proposed to be responsible for apoE fragmentation, the specific functions of different apoE fragments and their possible links with AD.
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References
Eisenberg DTA, Kuzawa CW, Hayes MG (2010) Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history. Am J Phys Anthropol 143:100–111. https://doi.org/10.1002/ajpa.21298
Saunders AM, Strittmatter WJ, Schmechel D et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43:1467–1472
Elliott DA, Kim WS, Jans DA, Garner B (2007) Apoptosis induces neuronal apolipoprotein-E synthesis and localization in apoptotic bodies. Neurosci Lett 416:206–210. https://doi.org/10.1016/j.neulet.2007.02.014
LaDu MJ, Gilligan SM, Lukens JR et al (1998) Nascent astrocyte particles differ from lipoproteins in CSF. J Neurochem 70:2070–2081
Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240:622–630
Herz J, Beffert U (2000) Apolipoprotein E receptors: linking brain development and Alzheimer’s disease. Nat Rev Neurosci 1:51–58. https://doi.org/10.1038/35036221
Aggerbeck LP, Wetterau JR, Weisgraber KH et al (1988) Human apolipoprotein E3 in aqueous solution. II. Properties of the amino- and carboxyl-terminal domains. J Biol Chem 263:6249–6258
Wetterau JR, Aggerbeck LP, Rall SC, Weisgraber KH (1988) Human apolipoprotein E3 in aqueous solution. I. Evidence for two structural domains. J Biol Chem 263:6240–6248
Li WH, Tanimura M, Luo CC et al (1988) The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution. J Lipid Res 29:245–271
Rall SC, Weisgraber KH, Mahley RW (1982) Human apolipoprotein E. The complete amino acid sequence. J Biol Chem 257:4171–4178
Hatters DM, Budamagunta MS, Voss JC, Weisgraber KH (2005) Modulation of apolipoprotein E structure by domain interaction: differences in lipid-bound and lipid-free forms. J Biol Chem 280:34288–34295. https://doi.org/10.1074/jbc.M506044200
Morrow JA, Segall ML, Lund-Katz S et al (2000) Differences in stability among the human apolipoprotein E isoforms determined by the amino-terminal domain. Biochemistry 39:11657–11666
Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923
Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890
Grundke-Iqbal I, Iqbal K, Tung YC et al (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917
Ihara Y, Nukina N, Miura R, Ogawara M (1986) Phosphorylated tau protein is integrated into paired helical filaments in Alzheimer’s disease. J Biochem (Tokyo) 99:1807–1810
Kosik KS, Joachim CL, Selkoe DJ (1986) Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc Natl Acad Sci USA 83:4044–4048
Namba Y, Tomonaga M, Kawasaki H et al (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt–Jakob disease. Brain Res 541:163–166
Richey PL, Siedlak SL, Smith MA, Perry G (1995) Apolipoprotein E interaction with the neurofibrillary tangles and senile plaques in Alzheimer disease: implications for disease pathogenesis. Biochem Biophys Res Commun 208:657–663. https://doi.org/10.1006/bbrc.1995.1389
Winkler K, Scharnagl H, Tisljar U et al (1999) Competition of Abeta amyloid peptide and apolipoprotein E for receptor-mediated endocytosis. J Lipid Res 40:447–455
Strittmatter WJ, Weisgraber KH, Huang DY et al (1993) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci USA 90:8098–8102
Verghese PB, Castellano JM, Garai K et al (2013) ApoE influences amyloid-β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci USA 110:E1807–E1816. https://doi.org/10.1073/pnas.1220484110
Bales KR, Verina T, Dodel RC et al (1997) Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet 17:263–264. https://doi.org/10.1038/ng1197-263
Irizarry MC, Rebeck GW, Cheung B et al (2000) Modulation of A beta deposition in APP transgenic mice by an apolipoprotein E null background. Ann N Y Acad Sci 920:171–178
Wood SJ, Chan W, Wetzel R (1996) Seeding of A beta fibril formation is inhibited by all three isotypes of apolipoprotein E. Biochemistry 35:12623–12628. https://doi.org/10.1021/bi961074j
Hashimoto T, Serrano-Pozo A, Hori Y et al (2012) Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J Neurosci Off J Soc Neurosci 32:15181–15192. https://doi.org/10.1523/JNEUROSCI.1542-12.2012
Uchihara T, Duyckaerts C, He Y et al (1995) ApoE immunoreactivity and microglial cells in Alzheimer’s disease brain. Neurosci Lett 195:5–8. https://doi.org/10.1016/0304-3940(95)11763-M
Ulrich JD, Ulland TK, Mahan TE et al (2018) ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med 215:1047–1058. https://doi.org/10.1084/jem.20171265
Strittmatter WJ, Weisgraber KH, Goedert M et al (1994) Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp Neurol 125:163–171; discussion 172–174
Harris FM, Brecht WJ, Xu Q et al (2004) Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. J Biol Chem 279:44795–44801. https://doi.org/10.1074/jbc.M408127200
Tesseur I, Van Dorpe J, Spittaels K et al (2000) Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol 156:951–964. https://doi.org/10.1016/S0002-9440(10)64963-2
Genis I, Gordon I, Sehayek E, Michaelson DM (1995) Phosphorylation of tau in apolipoprotein E-deficient mice. Neurosci Lett 199:5–8
Shi Y, Yamada K, Liddelow SA et al (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523–527. https://doi.org/10.1038/nature24016
Elliott DA, Tsoi K, Holinkova S et al (2011) Isoform-specific proteolysis of apolipoprotein-E in the brain. Neurobiol Aging 32:257–271. https://doi.org/10.1016/j.neurobiolaging.2009.02.006
Brecht WJ, Harris FM, Chang S et al (2004) Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci Off J Soc Neurosci 24:2527–2534. https://doi.org/10.1523/JNEUROSCI.4315-03.2004
Marques MA, Tolar M, Harmony JA, Crutcher KA (1996) A thrombin cleavage fragment of apolipoprotein E exhibits isoform-specific neurotoxicity. Neuroreport 7:2529–2532
Tolar M, Marques MA, Harmony JA, Crutcher KA (1997) Neurotoxicity of the 22 kDa thrombin-cleavage fragment of apolipoprotein E and related synthetic peptides is receptor-mediated. J Neurosci Off J Soc Neurosci 17:5678–5686
Tolar M, Keller JN, Chan S et al (1999) Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity. J Neurosci Off J Soc Neurosci 19:7100–7110
Zhou W, Scott SA, Shelton SB, Crutcher KA (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
Harris FM, Brecht WJ, Xu Q et al (2003) Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci USA 100:10966–10971. https://doi.org/10.1073/pnas.1434398100
Tamboli IY, Heo D, Rebeck GW (2014) Extracellular proteolysis of apolipoprotein E (apoE) by secreted serine neuronal protease. PloS One 9:e93120. https://doi.org/10.1371/journal.pone.0093120
Chu Q, Diedrich JK, Vaughan JM et al (2016) HtrA1 proteolysis of ApoE in vitro is allele selective. J Am Chem Soc 138:9473–9478. https://doi.org/10.1021/jacs.6b03463
Muñoz SS, Li H, Ruberu K et al (2018) The serine protease HtrA1 contributes to the formation of an extracellular 25-kDa apolipoprotein E fragment that stimulates neuritogenesis. J Biol Chem. https://doi.org/10.1074/jbc.RA117.001278
Cho HS, Hyman BT, Greenberg SM, Rebeck GW (2001) Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in Abeta aggregation. J Neuropathol Exp Neurol 60:342–349
Wernette-Hammond ME, Lauer SJ, Corsini A et al (1989) Glycosylation of human apolipoprotein E. The carbohydrate attachment site is threonine 194. J Biol Chem 264:9094–9101
Aizawa Y, Fukatsu R, Takamaru Y et al (1997) Amino-terminus truncated apolipoprotein E is the major species in amyloid deposits in Alzheimer’s disease-affected brains: a possible role for apolipoprotein E in Alzheimer’s disease. Brain Res 768:208–214
Huang Y, Liu XQ, Wyss-Coray T et al (2001) Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc Natl Acad Sci USA 98:8838–8843. https://doi.org/10.1073/pnas.151254698
Love JE, Day RJ, Gause JW 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
Rohn TT, Catlin LW, Coonse KG, Habig JW (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
Gause JW, Day RJ, Caraway CA et al (2017) Evaluation of apolipoprotein E fragmentation as a biomarker for Alzheimer’s disease. J Neurol Neurol Disord. https://doi.org/10.15744/2454-4981.3.204
Mucke L, Masliah E, Yu G-Q et al (2000) High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 20:4050–4058. https://doi.org/10.1523/JNEUROSCI.20-11-04050.2000
Bien-Ly N, Andrews-Zwilling Y, Xu Q et al (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 USA 108:4236–4241. https://doi.org/10.1073/pnas.1018381108
Chang S, ran Ma T, Miranda RD et al (2005) Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity. Proc Natl Acad Sci USA 102:18694–18699. https://doi.org/10.1073/pnas.0508254102
Crutcher KA, Clay MA, Scott SA et al (1994) Neurite degeneration elicited by apolipoprotein E peptides. Exp Neurol 130:120–126. https://doi.org/10.1006/exnr.1994.1191
Clay MA, Anantharamaiah GM, Mistry MJ et al (1995) Localization of a domain in apolipoprotein E with both cytostatic and cytotoxic activity. Biochemistry 34:11142–11151
Laskowitz DT, Thekdi AD, Thekdi SD et al (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
Lynch JR, Tang W, Wang H et al (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
Aono M, Bennett ER, Kim KS et al (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
Li F-Q, Sempowski GD, McKenna SE et al (2006) Apolipoprotein E-derived peptides ameliorate clinical disability and inflammatory infiltrates into the spinal cord in a murine model of multiple sclerosis. J Pharmacol Exp Ther 318:956–965. https://doi.org/10.1124/jpet.106.103671
McAdoo JD, Warner DS, Goldberg RN et al (2005) Intrathecal administration of a novel apoE-derived therapeutic peptide improves outcome following perinatal hypoxic-ischemic injury. Neurosci Lett 381:305–308. https://doi.org/10.1016/j.neulet.2005.02.036
Gay EA, Klein RC, Yakel JL (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
Gay EA, Bienstock RJ, Lamb PW, Yakel JL (2007) Structural determinates for apolipoprotein E-derived peptide interaction with the alpha7 nicotinic acetylcholine receptor. Mol Pharmacol 72:838–849. https://doi.org/10.1124/mol.107.035527
Klein RC, Yakel JL (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
Wellnitz S, Friedlein A, Bonanni C et al (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
Dafnis I, Stratikos E, Tzinia A et al (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
Dafnis I, Argyri L, Sagnou M et al (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
Dafnis I, Tzinia AK, Tsilibary EC et al (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
Rohn TT (2013) Proteolytic cleavage of apolipoprotein E4 as the keystone for the heightened risk associated with Alzheimer’s disease. Int J Mol Sci 14:14908–14922. https://doi.org/10.3390/ijms140714908
Lin Y-T, Seo J, Gao F et al (2018) APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98:1141–1154.e7. https://doi.org/10.1016/j.neuron.2018.05.008
Wang C, Najm R, Xu Q 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
Huang Y-WA, Zhou B, Wernig M, Südhof TC (2017) ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and Aβ secretion. Cell 168:427–441.e21. https://doi.org/10.1016/j.cell.2016.12.044
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Lezanne Ooi is supported by a National Health and Medical Research Council of Australia (NHMRC) Boosting Dementia Research Leadership Fellowship (Grant no. APP1135720).
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Special Issue: In honor of Prof. Anthony J. Turner.
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Muñoz, S.S., Garner, B. & Ooi, L. Understanding the Role of ApoE Fragments in Alzheimer’s Disease. Neurochem Res 44, 1297–1305 (2019). https://doi.org/10.1007/s11064-018-2629-1
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DOI: https://doi.org/10.1007/s11064-018-2629-1