Parkin prevents cortical atrophy and Aβ-induced alterations of brain metabolism: ¹³C NMR and magnetic resonance imaging studies in AD models

Neuroscience. 2012 Dec 6:225:22-34. doi: 10.1016/j.neuroscience.2012.08.057. Epub 2012 Sep 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / therapy*
  • Amyloid beta-Peptides / toxicity*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Aspartic Acid / metabolism
  • Atrophy / etiology
  • Atrophy / prevention & control
  • Brain* / drug effects
  • Brain* / metabolism
  • Brain* / pathology
  • Carbon Isotopes
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Eukaryotic Initiation Factors
  • Gene Knock-In Techniques
  • Genetic Vectors
  • Glial Fibrillary Acidic Protein / metabolism
  • Glutamic Acid / metabolism
  • Humans
  • Magnetic Resonance Imaging
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mice, Transgenic
  • Peptide Fragments / toxicity*
  • Phosphoproteins / metabolism
  • Presenilin-1 / genetics
  • Single-Blind Method
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • tau Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Carbon Isotopes
  • Carrier Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Eif4ebp1 protein, mouse
  • Elf4 protein, mouse
  • Eukaryotic Initiation Factors
  • Glial Fibrillary Acidic Protein
  • PSEN1 protein, human
  • Peptide Fragments
  • Phosphoproteins
  • Presenilin-1
  • Transcription Factors
  • amyloid beta-protein (1-42)
  • tau Proteins
  • Aspartic Acid
  • Glutamic Acid
  • Ubiquitin-Protein Ligases
  • parkin protein
  • TOR Serine-Threonine Kinases