Abstract
Direct (intracisternal) injection of aluminum complexes into rabbit brain results in a number of similarities with the neuropathological and biochemical changes observed in Alzheimer's disease and provides the opportunity to assess early events in neurodegeneration. This mode of administration induces cytochrome c release from mitochondria, a decrease in Bcl-2 in both mitochondria and endoplasmic reticulum, Bax translocation into mitochondria, activation of caspase-3, and DNA fragmentation. Coadministration of glial cell neuronal-derived factor (GDNF) inhibits these Bcl-2 and Bax changes, upregulates Bcl-XL, and abolishes the caspase-3 activity. Furthermore, treatment with GDNF dramatically inhibits apoptosis, as assessed by the TUNEL technique for detecting DNA damage. Treatment with GDNF may represent a therapeutic strategy to reverse the neuronal death associated with Alzheimer's disease and may exert its effect on apoptosis-regulatory proteins.
Copyright 2001 Academic Press.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alzheimer Disease / drug therapy
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Alzheimer Disease / metabolism
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Animals
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Apoptosis / drug effects*
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Caspase 3
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Caspases / metabolism
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Cisterna Magna
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Cytochrome c Group / metabolism
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DNA Fragmentation
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Drug Evaluation, Preclinical
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Endoplasmic Reticulum / metabolism
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Female
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Gene Expression Regulation / drug effects
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Genes, bcl-2
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Glial Cell Line-Derived Neurotrophic Factor
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Hippocampus / drug effects*
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Hippocampus / metabolism
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Hippocampus / pathology
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In Situ Nick-End Labeling
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Injections
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Mitochondria / metabolism*
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Nerve Growth Factors*
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Nerve Tissue Proteins / biosynthesis*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / pharmacology
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Nerve Tissue Proteins / therapeutic use*
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Neurons / drug effects*
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Neurons / metabolism
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Neurons / pathology
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Organometallic Compounds / administration & dosage
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Organometallic Compounds / toxicity
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Protein Transport / drug effects
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Pyrones / administration & dosage
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Pyrones / toxicity
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Rabbits
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bcl-2-Associated X Protein
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bcl-X Protein
Substances
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Cytochrome c Group
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Glial Cell Line-Derived Neurotrophic Factor
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Nerve Growth Factors
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Nerve Tissue Proteins
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Organometallic Compounds
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyrones
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bcl-2-Associated X Protein
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bcl-X Protein
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aluminum maltolate
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Caspase 3
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Caspases