Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 5, Pages 2683-2692Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M506646200
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- NCRR NIH HHS [C06 RR18928] Funding Source: Medline
- NIA NIH HHS [P01 AG022074] Funding Source: Medline
- NINDS NIH HHS [R21 NS046465] Funding Source: Medline
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We previously demonstrated that apolipoprotein E4 (apoE4) potentiates lysosomal leakage and apoptosis induced by amyloid beta (A beta) peptide in cultured Neuro-2a cells and hypothesized that the low pH of lysosomes accentuates the conversion of apoE4 to a molten globule, inducing reactive intermediates capable of destabilizing cellular membranes. Here we report that neutralizing lysosomal pH with bafilomycin or NH4Cl abolished the apoE4 potentiation of A beta-induced lysosomal leakage and apoptosis in Neuro-2a cells. Consistent with these results, apoE4 at acidic pH bound more avidly to phospholipid vesicles and disrupted them to a greater extent than at pH 7.4. Comparison of Arctic mutant A beta, which forms multimers, and GM6 mutant A beta, which remains primarily monomeric, showed that aggregation is essential for apoE4 to potentiate A beta-induced lysosomal leakage and apoptosis. Both apoE4 and A beta 1-42 had to be internalized to exert these effects. Blocking the low density lipoprotein receptor-related protein with small interfering RNA abolished the enhanced effects of apoE4 and A beta on lysosomes and apoptosis. In cultured Neuro-2a cells, A beta 1-42 increased lysosome formation to a greater extent in apoE3- or apoE4-transfected cells than in Neo-transfected cells, as shown by immunostaining for lysosome-associated membrane protein 1. Similarly, in transgenic mice expressing apoE and amyloid precursor protein, hippocampal neurons displayed increased numbers of lysosomes. Thus, apoE4 and A beta 1-42 may work in concert in neurons to increase lysosome formation while increasing the susceptibility of lysosomal membranes to disruption, release of lysosomal enzymes into the cytosol, and neuronal degeneration.
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