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Abnormal Glutamate Transport Function in Mutant Amyloid Precursor Protein Transgenic Mice

https://doi.org/10.1006/exnr.2000.7386Get rights and content

Abstract

Recent studies have shown that amyloid precursor protein (APP), which plays a central role in Alzheimer's disease (AD), protects against excitotoxic neuronal injuries by regulating the function of the glial glutamate transporters. The mechanisms underlying these effects and their relationship to the neurodegenerative process in AD are under intense scrutiny. In this context, the main objective of the present study was to determine if overexpression of mutant human APP in transgenic mouse brains results in altered functioning of the excitatory amino acid transporters (EAATs). Transgenic mice expressing the 695 amino acid form of the human APP from the Thy-1 promoter showed a significant decrease in Bmax and KD for aspartate uptake when compared to nontransgenic controls. This decrease in glutamate transporter activity was associated with decreased protein expression of glial specific glutamate transporters, EAAT1 and 2, but did not affect mRNA levels. These results suggest that expression of mutant forms of APP disturbs astroglial transport of excitatory amino acids at the posttranscriptional level leading, in turn, to increased susceptibility to glutamate toxicity.

References (36)

  • D.J Selkoe

    Amyloid β protein precursor and the pathogenesis of Alzheimer's disease

    Cell

    (1989)
  • M. Simpson et al.

    Reduced d-[3H]asparate binding in Down's syndrome brains

    Brain Res.

    (1989)
  • B.A Yankner

    Mechanisms of neuronal degeneration in Alzheimer's disease

    Neuron

    (1996)
  • A.J. Anderson et al.

    DNA damage and apoptosis in Alzheimer's disease: Colocalization with c-Jun immunoreactivity, relationship to brain area and effect of postmortem delay

    J. Neurosci.

    (1996)
  • F. Checler

    Processing of the β-amyloid precursor protein and its regulation in Alzheimer's disease

    J. Neurochem.

    (1995)
  • M. Citron et al.

    Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice

    Nature Med.

    (1997)
  • M. Citron et al.

    Mutation in the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production

    Nature

    (1992)
  • Cited by (0)

    1

    Present address: Department of Functional Genomics, Jahnsen Research Foundation, B-2340, Beerse, Belgium.

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