title: Parkin prevents cortical atrophy and Aβ-induced alterations of brain metabolism: ¹³C NMR and magnetic resonance imaging studies in AD models.
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.
authors.affiliation: Department of Neuroscience, Laboratory for Dementia and Parkinsonism, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: Norah
authors.initials: N
authors.lastname: Algarzae
authors.forename: Michaeline
authors.initials: M
authors.lastname: Hebron
authors.forename: Matthew
authors.initials: M
authors.lastname: Miessau
authors.forename: Charbel E-H
authors.initials: CE
authors.lastname: Moussa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001284:Atrophy / Q000209:etiology / Q000517:prevention & control; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002247:Carbon Isotopes; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D039642:Eukaryotic Initiation Factors; D055879:Gene Knock-In Techniques; D005822:Genetic Vectors; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000633:toxicity*; D010750:Phosphoproteins / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D016037:Single-Blind Method; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002247:Carbon Isotopes; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C499527:Eif4ebp1 protein, mouse; C491779:Elf4 protein, mouse; D039642:Eukaryotic Initiation Factors; D005904:Glial Fibrillary Acidic Protein; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D010750:Phosphoproteins; D053764:Presenilin-1; D014157:Transcription Factors; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D001224:Aspartic Acid; D018698:Glutamic Acid; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D058570:TOR Serine-Threonine Kinases