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Originally published In Press as doi:10.1074/jbc.M112109200 on March 23, 2002

J. Biol. Chem., Vol. 277, Issue 24, 21821-21828, June 14, 2002
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Apolipoprotein E4 Potentiates Amyloid beta  Peptide-induced Lysosomal Leakage and Apoptosis in Neuronal Cells*

Zhong-Sheng JiDagger , R. Dennis MirandaDagger , Yvonne M. NewhouseDagger , Karl H. WeisgraberDagger §, Yadong HuangDagger , and Robert W. MahleyDagger §||**

From the Dagger  Gladstone Institute of Neurological Disease, § Cardiovascular Research Institute, and Departments of || Medicine and  Pathology, University of California, San Francisco, California 94141-9100

We assessed the isoform-specific effects of apolipoprotein (apo) E on the response of Neuro-2a cells to the amyloid beta  peptide (Abeta 1-42). As determined by the intracellular staining pattern and the release of beta -hexosaminidase into the cytosol, apoE4-transfected cells treated with aggregated Abeta 1-42 showed a greater tendency toward lysosomal leakage than neo- or apoE3-transfected cells. Abeta 1-42 caused significantly greater cell death and more than 2-fold greater DNA fragmentation in apoE4-secreting than in apoE3-secreting or control cells. H2O2 or staurosporine enhanced cell death and apoptosis in apoE4-transfected cells but not in apoE3-transfected cells. A caspase-9 inhibitor abolished the potentiation of Abeta 1-42-induced apoptosis by apoE4. Similar results were obtained with conditioned medium from cells secreting apoE3 or apoE4. Cells preincubated for 4 h with a source of apoE3 or apoE4, followed by removal of apoE from the medium and from the cell surface, still exhibited the isoform-specific response to Abeta 1-42, indicating that the potentiation of apoptosis required intracellular apoE, presumably in the endosomes or lysosomes. Studies of phospholipid (dimyristoylphosphatidylcholine) bilayer vesicles encapsulating 5-(and-6)-carboxyfluorescein dye showed that apoE4 remodeled and disrupted the phospholipid vesicles to a greater extent than apoE3 or apoE2. In response to Abeta 1-42, vesicles containing apoE4 were disrupted to a greater extent than those containing apoE3. These findings are consistent with apoE4 forming a reactive molecular intermediate that avidly binds phospholipid and may insert into the lysosomal membrane, destabilizing it and causing lysosomal leakage and apoptosis in response to Abeta 1-42.

* This work was supported in part by Program Project Grant HL47660 from the National Institutes of Health and Grant 8RT-0130 from the University of California Tobacco-related Disease Research Program.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Gladstone Inst. of Neurological Disease, P. O. Box 419100, San Francisco, CA 94141-9100. Tel.: 415-826-7500; Fax: 415-285-5632; E-mail: rmahley@gladstone.ucsf.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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