Abstract
Most Down's syndrome (DS) patients develop Alzheimer's disease (AD) neuropathology. Astrocyte and neuronal cultures derived from fetal DS brain show alterations in the processing of amyloid beta precursor protein (AbetaPP), including increased levels of AbetaPP and C99, reduced levels of secreted AbetaPP (AbetaPPs) and C83, and intracellular accumulation of insoluble Abeta42. This pattern of AbetaPP processing is recapitulated in normal astrocytes by inhibition of mitochondrial metabolism, consistent with impaired mitochondrial function in DS astrocytes. Intracellular Abeta42 and reduced AbetaPPs are also detected in DS and AD brains. The survival of DS neurons is markedly increased by recombinant or astrocyte-produced AbetaPPs, suggesting that AbetaPPs may be a neuronal survival factor. Thus, mitochondrial dysfunction in DS may lead to intracellular deposition of Abeta42, reduced levels of AbetaPPs, and a chronic state of increased neuronal vulnerability.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adolescent
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Adult
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Aged
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Aged, 80 and over
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Alzheimer Disease / etiology
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / metabolism
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Amyloid beta-Protein Precursor / metabolism*
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Amyloid beta-Protein Precursor / pharmacology
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Apoptosis
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Astrocytes / cytology
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Astrocytes / drug effects
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Astrocytes / metabolism*
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Benzimidazoles / metabolism
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Carbocyanines / metabolism
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Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
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Cell Survival
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Cells, Cultured
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Cerebral Cortex / embryology
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Cerebral Cortex / metabolism
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Cerebral Cortex / pathology
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Child
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Child, Preschool
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Down Syndrome / complications
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Down Syndrome / metabolism*
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Down Syndrome / pathology
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Fetus / cytology
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Fluorescent Dyes / metabolism
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Hippocampus / metabolism
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Hippocampus / pathology
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Humans
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Immunohistochemistry
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In Situ Nick-End Labeling
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Infant
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Middle Aged
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Neurons / cytology
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Neurons / metabolism
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Peptide Fragments / metabolism
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Recombinant Proteins / pharmacology
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Uncoupling Agents / metabolism
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Benzimidazoles
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Carbocyanines
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Fluorescent Dyes
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Peptide Fragments
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Recombinant Proteins
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Uncoupling Agents
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amyloid beta-protein (1-42)
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5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine
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Carbonyl Cyanide m-Chlorophenyl Hydrazone