Abnormal glutamate transport function in mutant amyloid precursor protein transgenic mice

Recent studies have shown that amyloid precursor protein (APP), which plays a central role in Alzheimer's disease (AD), protects against excitotoxic n euronal injuries by regulating the function of the glial glutamate transpor ters. The mechanisms underlying these effects and their relationship to the neurodegenerative process in AD are under intense scrutiny. In this contex t, the main objective of the present study was to determine if overexpressi on of mutant human APP in transgenic mouse brains results in altered functi oning of the excitatory amino acid transporters (EAATs). Transgenic mice ex pressing the 695 amino acid form of the human APP from the Thy-1 promoter s howed a significant decrease in B-max and K-D for aspartate uptake when com pared to nontransgenic controls. This decrease in glutamate transporter act ivity was associated with decreased protein expression of glial specific gl utamate transporters, EAAT1 and 2, but did not affect mRNA levels. These re sults suggest that expression of mutant forms of APP disturbs astroglial tr ansport of excitatory amino acids at the posttranscriptional level leading, in turn, to increased susceptibility to glutamate toxicity. (C) 2000 Acade mic Press.