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 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 B(max) and K(D) 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.
Masliah
E
E
Department of Neurosciences, University of California at San Diego, La Jolla, California, USA.
Alford
M
M
Mallory
M
M
Rockenstein
E
E
Moechars
D
D
Van Leuven
F
F
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D016564:Amyloid beta-Protein Precursor; D012333:RNA, Messenger