Isoform-specific proteolysis of apolipoprotein-E in the brain

Neurobiology of Aging

Volumn 32, Issue 2, 2011, Pages 257-271

  Elliott, David A ^a   Tsoi, Kayan ^a   Holinkova, Sandra ^a   Chan, Sharon L ^a   Kim, Woojin S ^a,b   Halliday, Glenda M ^a,b   Rye, Kerry Anne ^c   Garner, Brett ^a,b  

^a NEUROSCIENCE RESEARCH AUSTRALIA   (Australia)

^b UNIVERSITY OF NEW SOUTH WALES   (Australia)

^c HEART RESEARCH INSTITUTE   (Australia)

Author keywords

Alzheimer's disease; ApoE; ApoE Fragmentation; Cathepsin D; Human brain

Indexed keywords

APOLIPOPROTEIN E3; APOLIPOPROTEIN E4; CATHEPSIN D; GUANIDINE; PEPTIDE; SODIUM CHLORIDE; TRITON X 100;

AGED; ALZHEIMER DISEASE; ARTICLE; BRAIN HOMOGENATE; CEREBELLUM; CLINICAL ARTICLE; CONTROLLED STUDY; FEMALE; FRONTAL CORTEX; HIPPOCAMPUS; HUMAN; HUMAN TISSUE; MALE; OCCIPITAL LOBE; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN DETERMINATION; PROTEIN LOCALIZATION; PROTEIN PROCESSING;

AGED; AGED, 80 AND OVER; ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; APOLIPOPROTEIN E3; APOLIPOPROTEIN E4; APOLIPOPROTEINS E; BRAIN; CATHEPSIN D; CELL LINE, TUMOR; ENZYME-LINKED IMMUNOSORBENT ASSAY; FEMALE; HEMOSTATICS; HUMANS; MALE; MIDDLE AGED; NEUROBLASTOMA; PEPTIDE FRAGMENTS; PROTEIN ISOFORMS; STATISTICS, NONPARAMETRIC; THROMBIN; TRANSFECTION;

EID: 78649817606     PISSN: 01974580     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.neurobiolaging.2009.02.006     Document Type: Article

References (84)

1. Aizawa Y., Fukatsu R., Takamaru Y., Tsuzuki K., Chiba H., Kobayashi K., Fujii N., Takahata N. 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. 1997, 768:208-214.
2. Aleshkov S., Abraham C.R., Zannis V.I. Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40). Relevance to Alzheimer's disease. Biochemistry 1997, 36:10571-10580.
3. Aono M., Bennett E.R., Kim K.S., Lynch J.R., Myers J., Pearlstein R.D., Warner D.S., Laskowitz D.T. Protective effect of apolipoprotein E-mimetic peptides on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cell cultures. Neuroscience 2003, 116:437-445.
4. Arai H., Kashiwagi S., Nagasaka Y., Uchida K., Hoshii Y., Nakamura K. Oxidative modification of apolipoprotein E in human very-low-density lipoprotein and its inhibition by glycosaminoglycans. Arch. Biochem. Biophys. 1999, 367:1-8.
5. Arai T., Miklossy J., Klegeris A., Guo J.P., McGeer P.L. Thrombin and prothrombin are expressed by neurons and glial cells and accumulate in neurofibrillary tangles in Alzheimer disease brain. J. Neuropathol. Exp. Neurol. 2006, 65:19-25.
6. Barbier A., Clement-Collin V., Dergunov A.D., Visvikis A., Siest G., Aggerbeck L.P. The structure of human apolipoprotein E2, E3 and E4 in solution 1. Tertiary and quaternary structure. Biophys. Chem. 2006, 119:158-169.
7. Beffert U., Aumont N., Dea D., Lussier-Cacan S., Davignon J., Poirier J. Apolipoprotein E isoform-specific reduction of extracellular amyloid in neuronal cultures. Brain Res. Mol. Brain Res. 1999, 68:181-185.
8. Bell R.D., Sagare A.P., Friedman A.E., Bedi G.S., Holtzman D.M., Deane R., Zlokovic B.V. Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J. Cereb. Blood Flow Metab. 2007, 27:909-918.
9. Boschert U., Merlo-Pich E., Higgins G., Roses A.D., Catsicas S. Apolipoprotein E expression by neurons surviving excitotoxic stress. Neurobiol. Dis. 1999, 6:508-514.
10. 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., Mahley R.W., Huang Y. Neuron-specific apolipoprotein e{open}4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 2004, 24:2527-2534.
11. Castano E.M., Prelli F., Pras M., Frangione B. Apolipoprotein E carboxyl-terminal fragments are complexed to amyloids A and L. Implications for amyloidogenesis and Alzheimer's disease. J. Biol. Chem. 1995, 270:17610-17615.
12. Cataldo A.M., Nixon R.A. Enzymatically active lysosomal proteases are associated with amyloid deposits in Alzheimer brain. Proc. Natl. Acad. Sci. U S A 1990, 87:3861-3865.
13. Cataldo A.M., Paskevich P.A., Kominami E., Nixon R.A. Lysosomal hydrolases of different classes are abnormally distributed in brains of patients with Alzheimer disease. Proc. Natl. Acad. Sci. U S A 1991, 88:10998-11002.
14. Chang S., ran Ma T., Miranda R.D., Balestra M.E., Mahley R.W., Huang Y. 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 2005, 102:18694-18699.
15. Cho H.S., Hyman B.T., Greenberg S.M., Rebeck G.W. Quantitation of apoE domains in Alzheimer disease brain suggests a role for apoE in Abeta aggregation. J. Neuropathol. Exp. Neurol. 2001, 60:342-349.
16. Clay M.A., Anantharamaiah G.M., Mistry M.J., Balasubramaniam A., Harmony J.A. Localization of a domain in apolipoprotein E with both cytostatic and cytotoxic activity. Biochemistry 1995, 34:11142-11151.
17. Clement-Collin V., Barbier A., Dergunov A.D., Visvikis A., Siest G., Desmadril M., Takahashi M., Aggerbeck L.P. The structure of human apolipoprotein E2, E3 and E4 in solution. 2. Multidomain organization correlates with the stability of apoE structure. Biophys. Chem. 2006, 119:170-185.
18. Corder E.H., Saunders A.M., Strittmatter W.J., Schmechel D.E., Gaskell P.C., Small G.W., Roses A.D., Haines J.L., Pericak-Vance M.A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993, 261:921-923.
19. Crutcher K.A., Clay M.A., Scott S.A., Tian X., Tolar M., Harmony J.A. Neurite degeneration elicited by apolipoprotein E peptides. Exp. Neurol. 1994, 130:120-126.
20. Dupont-Wallois L., Soulie C., Sergeant N., Wavrant-de Wrieze N., Chartier-Harlin M.C., Delacourte A., Caillet-Boudin M.L. ApoE synthesis in human neuroblastoma cells. Neurobiol. Dis. 1997, 4:356-364.
21. Elliott D.A., Kim W.S., Jans D.A., Garner B. Apoptosis induces neuronal apolipoprotein-E synthesis and localization in apoptotic bodies. Neurosci. Lett. 2007, 416:206-210.
22. Fagan A.M., Holtzman D.M., Munson G., Mathur T., Schneider D., Chang L.K., Getz G.S., Reardon C.A., Lukens J., Shah J.A., LaDu M.J. Unique lipoproteins secreted by primary astrocytes from wild type, apoE (-/-), and human apoE transgenic mice. J. Biol. Chem. 1999, 274:30001-30007.
23. Gay E.A., Bienstock R.J., Lamb P.W., Yakel J.L. Structural determinates for apolipoprotein E-derived peptide interaction with the alpha7 nicotinic acetylcholine receptor. Mol. Pharmacol. 2007, 72:838-849.
24. Golabek A.A., Kida E., Walus M., Perez C., Wisniewski T., Soto C. Sodium dodecyl sulfate-resistant complexes of Alzheimer's amyloid beta-peptide with the N-terminal, receptor binding domain of apolipoprotein E. Biophys. J. 2000, 79:1008-1015.
25. 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., Weisgraber K.H., Mucke L., Mahley R.W., Huang Y. Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc. Natl. Acad. Sci. U S A 2003, 100:10966-10971.
26. Hayashi H., Campenot R.B., Vance D.E., Vance J.E. Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1. J. Neurosci. 2007, 27:1933-1941.
27. Hirsch-Reinshagen V., Maia L.F., Burgess B.L., Blain J.F., Naus K.E., McIsaac S.A., Parkinson P.F., Chan J.Y., Tansley G.H., Hayden M.R., Poirier J., Van Nostrand W., Wellington C.L. The absence of ABCA1 decreases soluble apoE levels but does not diminish amyloid deposition in two murine models of Alzheimer's disease. J. Biol. Chem. 2005, 280:43243-43256.
28. Hoe H.S., Harris D.C., Rebeck G.W. Multiple pathways of apolipoprotein E signaling in primary neurons. J. Neurochem. 2005, 93:145-155.
29. Huang Y., Liu X.Q., Wyss-Coray T., Brecht W.J., Sanan D.A., Mahley R.W. Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc. Natl. Acad. Sci. U S A 2001, 98:8838-8843.
30. Innerarity T.L., Weisgraber K.H., Arnold K.S., Rall S.C., Mahley R.W. Normalization of receptor binding of apolipoprotein E2. Evidence for modulation of the binding site conformation. J. Biol. Chem. 1984, 259:7261-7267.
31. Jiang Q., Lee C.Y., Mandrekar S., Wilkinson B., Cramer P., Zelcer N., Mann K., Lamb B., Willson T.M., Collins J.L., Richardson J.C., Smith J.D., Comery T.A., Riddell D., Holtzman D.M., Tontonoz P., Landreth G.E. ApoE promotes the proteolytic degradation of Abeta. Neuron 2008, 58:681-693.
32. Jordan J., Galindo M.F., Miller R.J., Reardon C.A., Getz G.S., LaDu M.J. Isoform-specific effect of apolipoprotein E on cell survival and beta-amyloid-induced toxicity in rat hippocampal pyramidal neuronal cultures. J. Neurosci. 1998, 18:195-204.
33. Jung H., Lee E.Y., Lee S.I. Age-related changes in ultrastructural features of cathepsin B- and D-containing neurons in rat cerebral cortex. Brain Res. 1999, 844:43-54.
34. Kagedal K., Johansson U., Ollinger K. The lysosomal protease cathepsin D mediates apoptosis induced by oxidative stress. FASEB J. 2001, 15:1592-1594.
35. Kagedal K., Zhao M., Svensson I., Brunk U.T. Sphingosine-induced apoptosis is dependent on lysosomal proteases. Biochem. J. 2001, 359:335-343.
36. Kim W.S., Suryo Rahmanto A., Kamili A., Rye K.A., Guillemin G.J., Gelissen I.C., Jessup W., Hill A.F., Garner B. Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein-E discs and suppression of amyloid-beta peptide generation. J. Biol. Chem. 2007, 282:2851-2861.
37. LaDu M.J., Falduto M.T., Manelli A.M., Reardon C.A., Getz G.S., Frail D.E. Isoform-specific binding of apolipoprotein E to beta-amyloid. J. Biol. Chem. 1994, 269:23403-23406.
38. LaDu M.J., Gilligan S.M., Lukens J.R., Cabana V.G., Reardon C.A., Van Eldik L.J., Holtzman D.M. Nascent astrocyte particles differ from lipoproteins in CSF. J. Neurochem. 1998, 70:2070-2081.
39. Ladu M.J., Reardon C., Van Eldik L., Fagan A.M., Bu G., Holtzman D., Getz G.S. Lipoproteins in the central nervous system. Ann. N. Y. Acad. Sci. 2000, 903:167-175.
40. Laskowitz D.T., Thekdi A.D., Thekdi S.D., Han S.K., Myers J.K., Pizzo S.V., Bennett E.R. Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides. Exp. Neurol. 2001, 167:74-85.
41. Li F.Q., Sempowski G.D., McKenna S.E., Laskowitz D.T., Colton C.A., Vitek M.P. 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. 2006, 318:956-965.
42. Lu B., Morrow J.A., Weisgraber K.H. Conformational reorganization of the four-helix bundle of human apolipoprotein E in binding to phospholipid. J. Biol. Chem. 2000, 275:20775-20781.
43. Lynch J.R., Tang W., Wang H., Vitek M.P., Bennett E.R., Sullivan P.M., Warner D.S., Laskowitz D.T. ApoE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J. Biol. Chem. 2003, 278:48529-48533.
44. Lynch J.R., Wang H., Mace B., Leinenweber S., Warner D.S., Bennett E.R., Vitek M.P., McKenna S., Laskowitz D.T. A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury. Exp. Neurol. 2005, 192:109-116.
45. Mahley R.W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988, 240:622-630.
46. Mahley R.W., Nathan B.P., Pitas R.E. Apolipoprotein E. Structure, function, and possible roles in Alzheimer's disease. Ann. N. Y. Acad. Sci. 1996, 777:139-145.
47. Mahley R.W., Rall S.C. Apolipoprotein E: far more than a lipid transport protein. Annu. Rev. Genomics Hum. Genet. 2000, 1:507-537.
48. Marques M.A., Owens P.A., Crutcher K.A. Progress toward identification of protease activity involved in proteolysis of apolipoprotein e in human brain. J. Mol. Neurosci. 2004, 24:73-80.
49. Marques M.A., Tolar M., Harmony J.A., Crutcher K.A. A thrombin cleavage fragment of apolipoprotein E exhibits isoform-specific neurotoxicity. Neuroreport 1996, 7:2529-2532.
50. Metzger R.E., LaDu M.J., Pan J.B., Getz G.S., Frail D.E., Falduto M.T. Neurons of the human frontal cortex display apolipoprotein E immunoreactivity: implications for Alzheimer's disease. J. Neuropathol. Exp. Neurol. 1996, 55:372-380.
51. Mhatre M., Nguyen A., Kashani S., Pham T., Adesina A., Grammas P. Thrombin, a mediator of neurotoxicity and memory impairment. Neurobiol. Aging 2004, 25:783-793.
52. Minarowska A., Gacko M., Karwowska A., Minarowski L. Human cathepsin D. Folia Histochem. Cytobiol. 2008, 46:23-38.
53. Mirra S.S., Heyman A., McKeel D., Sumi S.M., Crain B.J., Brownlee L.M., Vogel F.S., Hughes J.P., van Belle G., Berg L. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991, 41:479-486.
54. Miyata M., Smith J.D. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat. Genet. 1996, 14:55-61.
55. Morrow J.A., Arnold K.S., Weisgraber K.H. Functional characterization of apolipoprotein E isoforms overexpressed in Escherichia coli. Protein Expr. Purif. 1999, 16:224-230.
56. Morrow J.A., Hatters D.M., Lu B., Hochtl P., Oberg K.A., Rupp B., Weisgraber K.H. Apolipoprotein E4 forms a molten globule. A potential basis for its association with disease. J. Biol. Chem. 2002, 277:50380-50385.
57. Morrow J.A., Segall M.L., Lund-Katz S., Phillips M.C., Knapp M., Rupp B., Weisgraber K.H. Differences in stability among the human apolipoprotein E isoforms determined by the amino-terminal domain. Biochemistry 2000, 39:11657-11666.
58. NIA, 1997. Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Neurobiol. Aging 18, S1-2.
59. Pitas R.E., Boyles J.K., Lee S.H., Hui D., Weisgraber K.H. Lipoproteins and their receptors in the central nervous system. Characterization of the lipoproteins in cerebrospinal fluid and identification of apolipoprotein B,E(LDL) receptors in the brain. J. Biol. Chem. 1987, 262:14352-14360.
60. Quinn C.M., Kagedal K., Terman A., Stroikin U., Brunk U.T., Jessup W., Garner B. Induction of fibroblast apolipoprotein E expression during apoptosis, starvation-induced growth arrest and mitosis. Biochem. J. 2004, 378:753-761.
61. Rall S.C., Weisgraber K.H., Innerarity T.L., Mahley R.W. Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc. Natl. Acad. Sci. U S A 1982, 79:4696-4700.
62. Rebeck G.W., LaDu M.J., Estus S., Bu G., Weeber E.J. The generation and function of soluble apoE receptors in the CNS. Mol. Neurodegener. 2006, 1:15.
63. Riddell D.R., Zhou H., Atchison K., Warwick H.K., Atkinson P.J., Jefferson J., Xu L., Aschmies S., Kirksey Y., Hu Y., Wagner E., Parratt A., Xu J., Li Z., Zaleska M.M., Jacobsen J.S., Pangalos M.N., Reinhart P.H. Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J. Neurosci. 2008, 28:11445-11453.
64. Roberg K., Kagedal K., Ollinger K. Microinjection of cathepsin d induces caspase-dependent apoptosis in fibroblasts. Am. J. Pathol. 2002, 161:89-96.
65. Rye K.A., Bright R., Psaltis M., Barter P.J. Regulation of reconstituted high density lipoprotein structure and remodeling by apolipoprotein E. J. Lipid Res. 2006, 47:1025-1036.
66. Saftig P., Hetman M., Schmahl W., Weber K., Heine L., Mossmann H., Koster A., Hess B., Evers M., von Figura K., et al. Mice deficient for the lysosomal proteinase cathepsin D exhibit progressive atrophy of the intestinal mucosa and profound destruction of lymphoid cells. EMBO J. 1995, 14:3599-3608.
67. Singh K., Chaturvedi R., Asim M., Barry D.P., Lewis N.D., Vitek M.P., Wilson K.T. The apolipoprotein E-mimetic peptide COG112 inhibits the inflammatory response to citrobacter rodentium in colonic epithelial cells by preventing NF-kappa B activation. J. Biol. Chem. 2008, 283:16752-16761.
68. Smirnova I.V., Salazar A., Arnold P.M., Glatt S., Handler M., Festoff B.W. Thrombin and its precursor in human cerebrospinal fluid. Thromb. Haemost. 1997, 78:1473-1479.
69. Strittmatter W.J., Saunders A.M., Schmechel D., Pericak-Vance M., Enghild J., Salvesen G.S., Roses A.D. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. U S A 1993, 90:1977-1981.
70. Strittmatter W.J., Weisgraber K.H., Goedert M., Saunders A.M., Huang D., Corder E.H., Dong L.M., Jakes R., Alberts M.J., Gilbert J.R., et al. Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp. Neurol. 1994, 125:163-171. discussion 72-74.
71. Tokuda T., Calero M., Matsubara E., Vidal R., Kumar A., Permanne B., Zlokovic B., Smith J.D., Ladu M.J., Rostagno A., Frangione B., Ghiso J. Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid beta peptides. Biochem. J. 2000, 348(Pt 2):359-365.
72. Tolar M., Keller J.N., Chan S., Mattson M.P., Marques M.A., Crutcher K.A. Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity. J. Neurosci. 1999, 19:7100-7110.
73. Tolar M., Marques M.A., Harmony J.A., Crutcher K.A. Neurotoxicity of the 22kDa thrombin-cleavage fragment of apolipoprotein E and related synthetic peptides is receptor-mediated. J. Neurosci. 1997, 17:5678-5686.
74. Weers P.M., Narayanaswami V., Choy N., Luty R., Hicks L., Kay C.M., Ryan R.O. Lipid binding ability of human apolipoprotein E N-terminal domain isoforms: correlation with protein stability?. Biophys. Chem. 2003, 100:481-492.
75. Weers P.M., Narayanaswami V., Ryan R.O. Modulation of the lipid binding properties of the N-terminal domain of human apolipoprotein E3. Eur. J. Biochem. 2001, 268:3728-3735.
76. Wellnitz S., Friedlein A., Bonanni C., Anquez V., Goepfert F., Loetscher H., Adessi C., Czech C. A 13kDa carboxy-terminal fragment of ApoE stabilizes Abeta hexamers. J. Neurochem. 2005, 94:1351-1360.
77. Wetterau J.R., Aggerbeck L.P., Rall S.C., Weisgraber K.H. Human apolipoprotein E3 in aqueous solution. I. Evidence for two structural domains. J. Biol. Chem. 1988, 263:6240-6248.
78. Wisniewski T., Lalowski M., Golabek A., Vogel T., Frangione B. Is Alzheimer's disease an apolipoprotein E amyloidosis?. Lancet 1995, 345:956-958.
79. Xu P.T., Gilbert J.R., Qiu H.L., Ervin J., Rothrock-Christian T.R., Hulette C., Schmechel D.E. Specific regional transcription of apolipoprotein E in human brain neurons. Am. J. Pathol. 1999, 154:601-611.
80. Xu Q., Brecht W.J., Weisgraber K.H., Mahley R.W., Huang Y. Apolipoprotein E4 domain interaction occurs in living neuronal cells as determined by fluorescence resonance energy transfer. J. Biol. Chem. 2004, 279:25511-25516.
81. Xu Q., Li Y., Cyras C., Sanan D.A., Cordell B. Isolation and characterization of apolipoproteins from murine microglia. Identification of a low density lipoprotein-like apolipoprotein J-rich but E-poor spherical particle. J. Biol. Chem. 2000, 275:31770-31777.
82. Zanni E.E., Kouvatsi A., Hadzopoulou-Cladaras M., Krieger M., Zannis V.I. Expression of ApoE gene in Chinese hamster cells with a reversible defect in O-glycosylation. Glycosylation is not required for apoE secretion. J. Biol. Chem. 1989, 264:9137-9140.
83. Zhang D., McQuade J.-A.M., Shockley K.P., Levin L., Marques M.A., Crutcher K.A. Proteolysis of apolipoprotein E and Alzheimer's disease pathology. Alzheimers Rep. 2001, 4:67-79.
84. Zhou W., Scott S.A., Shelton S.B., Crutcher K.A. Cathepsin D-mediated proteolysis of apolipoprotein E: possible role in Alzheimer's disease. Neuroscience 2006, 143:689-701.