Membrane localization of beta-amyloid 1-42 in lysosomes: a possible mechanism for lysosome labilization.
beta-Amyloid peptide (Abeta42) is the core protein of amyloid plaque in Alzheimer disease. The intracellular accumulation of Abeta42 in the endosomal/lysosomal system has been under investigation for many years, but the direct link between Abeta42 accumulation and dysfunction of the endosomal/lysosomal system is still largely unknown. Here, we found that both in vitro and in vivo, a major portion of Abeta42 was tightly inserted into and a small portion peripherally associated with the lysosomal membrane, whereas its soluble portion was minimal. We also found that the Abeta42 molecules inserted into the membrane tended to form multiple oligomeric aggregates, whereas Abeta40 peptides formed only dimers. Neutralizing lysosomal pH in differentiated PC12 cells decreased the lysosomal membrane insertion of Abeta42 and moderated Abeta42-induced lysosomal labilization and cytotoxicity. Our findings, thus, suggest that the membrane-inserted portion of Abeta42 accumulated in lysosomes may destabilize the lysosomal membrane and induce neurotoxicity.
Liu
Rui-Qin
RQ
State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Zhou
Qing-Hua
QH
Ji
Shang-Rong
SR
Zhou
Qiang
Q
Feng
Du
D
Wu
Yi
Y
Sui
Sen-Fang
SF
D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D008051:Lipid Bilayers / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D055503:Protein Multimerization; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008051:Lipid Bilayers; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D002738:Chloroquine