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Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice
E Masliah1, M Alford, M Mallory
1Department of Neurosciences, University of California at San Diego, La Jolla, California, USA.
Experimental Neurology
|June 2, 2000
Summary
Overexpression of mutant amyloid precursor protein (APP) in mice impairs glutamate transporter function. This dysfunction in excitatory amino acid transporters (EAATs) may increase susceptibility to excitotoxicity in Alzheimer's disease (AD).
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Amyloid precursor protein (APP) is crucial in Alzheimer's disease (AD).
- APP regulates glial glutamate transporters, offering protection against excitotoxic neuronal injury.
- Mechanisms linking APP, glutamate transport, and AD neurodegeneration require further investigation.
Purpose of the Study:
- To investigate the impact of mutant human APP overexpression on excitatory amino acid transporter (EAAT) function in transgenic mouse brains.
- To determine if altered APP influences the activity and expression of glial glutamate transporters.
Main Methods:
- Utilized transgenic mice overexpressing the 695 amino acid form of human APP under the Thy-1 promoter.
- Assessed aspartate uptake kinetics (Bmax and KD) in brain tissue.
- Quantified protein and mRNA levels of glial glutamate transporters (EAAT1 and EAAT2).
Main Results:
- Transgenic mice exhibited significantly reduced maximal aspartate uptake (Bmax) and altered affinity (KD) compared to controls.
- Glutamate transporter activity decrease correlated with reduced protein expression of EAAT1 and EAAT2.
- No significant changes were observed in the mRNA levels of EAAT1 and EAAT2.
Conclusions:
- Overexpression of mutant APP disrupts astroglial glutamate transport at a posttranscriptional level.
- Impaired EAAT function may lead to increased neuronal susceptibility to glutamate toxicity in AD.
- This study provides insights into the role of APP in neuroprotection and AD pathogenesis.
