PMID- 11162237
OWN - NLM
STAT- MEDLINE
DCOM- 20010524
LR  - 20220309
IS  - 0969-9961 (Print)
IS  - 0969-9961 (Linking)
VI  - 8
IP  - 1
DP  - 2001 Feb
TI  - Lysosomal membrane damage in soluble Abeta-mediated cell death in Alzheimer's 
      disease.
PG  - 19-31
AB  - Our previous studies suggest that a failure to degrade aggregated Abeta1-42 in 
      late endosomes or secondary lysosomes is a mechanism that contributes to 
      intracellular accumulation in Alzheimer's disease. In this study, we demonstrate 
      that cultured primary neurons are able to internalize soluble Abeta1-42 from the 
      culture medium and accumulate inside the endosomal/lysosomal system. The 
      intracellular Abeta1-42 is resistant to protease degradation and stable for at 
      least 48 h within the cultured neurons. Incubation of cultured neurons with a 
      cytotoxic concentration of soluble Abeta1-42 invokes the rapid free radical 
      generation within lysosomes and disruption of lysosomal membrane proton gradient 
      which precedes cell death. The loss of lysosomal membrane impermeability is only 
      specific to the Abeta1-42 isoform since incubation of cells with high 
      concentrations of Abeta1-40 has no effect on lysosomal hydrolase release. To 
      further support the role of lysosomal membrane damage in Abeta-mediated cell 
      death, we demonstrate that photodisruption of acridine orange (AO)-loaded 
      lysosomes with intense blue light induces a relatively rapid synchronous 
      lysosomal membrane damage and neuronal death similar to that observed as a result 
      of Abeta exposure. AO leaks quickly from late endosomes and lysosomes and 
      partially shifts the fluorescence from an orange fluorescence to a diffuse, green 
      cytoplasmic fluorescence. Such AO relocalization is due to an initial disruption 
      of the lysosomal proton gradient, followed by the release of lysosomal hydrolases 
      into the cytoplasmic compartment. Treatment of cells with either the antioxidant 
      n-propyl gallate or lysosomotropic amine (methylamine) partially blocks the 
      release of lysosomal contents suggesting that this AO relocalization is due to 
      lysosomal membrane oxidation. Based on these findings, we propose that the cell 
      death mediated by the soluble Abeta may be fundamentally different from the cell 
      loss observed following extracellular Abeta deposition.
CI  - Copyright 2001 Academic Press.
FAU - Ditaranto, K
AU  - Ditaranto K
AD  - Dementia Research Program, Nathan Kline Institute for Psychiatric Research, 
      Orangeburg, New York 10962, USA.
FAU - Tekirian, T L
AU  - Tekirian TL
FAU - Yang, A J
AU  - Yang AJ
LA  - eng
GR  - R01 AG025323/AG/NIA NIH HHS/United States
GR  - R01 MH059786/MH/NIMH NIH HHS/United States
GR  - F32 AG05817-02/AG/NIA NIH HHS/United States
GR  - R01 MH59786/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neurobiol Dis
JT  - Neurobiology of disease
JID - 9500169
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Antioxidants)
RN  - 0 (Oxidants, Photochemical)
RN  - 0 (Peptide Fragments)
RN  - 0 (amyloid beta-protein (1-40))
RN  - 0 (amyloid beta-protein (1-42))
SB  - IM
MH  - Alzheimer Disease/*pathology
MH  - Amino Acid Sequence
MH  - Amyloid beta-Peptides/*toxicity
MH  - Animals
MH  - Antioxidants/pharmacology
MH  - Cell Death/drug effects
MH  - Cells, Cultured
MH  - Lipid Peroxidation/drug effects
MH  - Lysosomes/*pathology
MH  - Membranes/pathology
MH  - Mice
MH  - Molecular Sequence Data
MH  - Oxidants, Photochemical/toxicity
MH  - Oxidation-Reduction
MH  - Peptide Fragments/toxicity
MH  - Rats
MH  - Up-Regulation/drug effects
EDAT- 2001/02/13 11:00
MHDA- 2001/05/26 10:01
CRDT- 2001/02/13 11:00
PHST- 2001/02/13 11:00 [pubmed]
PHST- 2001/05/26 10:01 [medline]
PHST- 2001/02/13 11:00 [entrez]
AID - S0969-9961(00)90364-4 [pii]
AID - 10.1006/nbdi.2000.0364 [doi]
PST - ppublish
SO  - Neurobiol Dis. 2001 Feb;8(1):19-31. doi: 10.1006/nbdi.2000.0364.