Abstract
Alzheimer's disease (AD) is a neurodegenerative aging disorder characterized by extracellular Aβ plaques and intraneuronal neurofibrillary tangles. We conducted longitudinal studies to examine the effects of Aβ on brain amino acid metabolism in lentiviral Aβ(1-42) gene transfer animals and transgenic AD mice. We also performed lentiviral parkin gene delivery to determine the effects of Aβ clearance in AD models. Aβ(1-42) activated mTOR signaling, and increased 4E-BP phosphorylation. Aβ(1-42) increased the synthesis of glutamate and aspartate, but not glutamine, leucine and isoleucine, but an increase in leucine and isoleucine levels was concurrent with diminution of neurotransmitters. Additionally, Aβ(1-42) attenuated mitochondrial tricarboxylic acid (TCA) cycle activity and decreased synthesis of its by-products. Glutamate levels increased prior to lactate accumulation, suggesting oxidative stress. Importantly, parkin reversed the effects of Aβ(1-42) on amino acid levels, prevented TCA cycle impairment and protected against glutamate toxicity. Cortical atrophy was observed in aged 3xTg-AD mice, while parkin expression was associated with reduced atrophy. Similarly, Aβ(1-42) resulted in significant cell loss, pronounced astrogliosis and cortical atrophy and parkin reduced astrogliosis and reversed Aβ(1-42) effects on cell loss and cortical atrophy. Taken together these data suggest that parkin prevents amyloid-induced alteration of brain metabolism and may be used as a therapeutic target to limit neuronal loss in AD.
Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Alzheimer Disease / complications
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Alzheimer Disease / genetics
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Alzheimer Disease / pathology*
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Alzheimer Disease / therapy*
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Amyloid beta-Peptides / toxicity*
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Amyloid beta-Protein Precursor / genetics
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Animals
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Aspartic Acid / metabolism
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Atrophy / etiology
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Atrophy / prevention & control
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Brain* / drug effects
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Brain* / metabolism
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Brain* / pathology
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Carbon Isotopes
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Carrier Proteins / metabolism
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Cell Cycle Proteins
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DNA-Binding Proteins / metabolism
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Disease Models, Animal
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Enzyme-Linked Immunosorbent Assay
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Eukaryotic Initiation Factors
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Gene Knock-In Techniques
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Genetic Vectors
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Glial Fibrillary Acidic Protein / metabolism
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Glutamic Acid / metabolism
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Humans
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Magnetic Resonance Imaging
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Magnetic Resonance Spectroscopy
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Mice
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Mice, Transgenic
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Peptide Fragments / toxicity*
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Phosphoproteins / metabolism
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Presenilin-1 / genetics
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Single-Blind Method
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TOR Serine-Threonine Kinases / metabolism
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Transcription Factors / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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tau Proteins / genetics
Substances
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Adaptor Proteins, Signal Transducing
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Carbon Isotopes
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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Eif4ebp1 protein, mouse
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Elf4 protein, mouse
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Eukaryotic Initiation Factors
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Glial Fibrillary Acidic Protein
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PSEN1 protein, human
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Peptide Fragments
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Phosphoproteins
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Presenilin-1
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Transcription Factors
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amyloid beta-protein (1-42)
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tau Proteins
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Aspartic Acid
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Glutamic Acid
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Ubiquitin-Protein Ligases
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parkin protein
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TOR Serine-Threonine Kinases