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Inhibition of AMPA responses by mutated presenilin 1

The inheritance of Alzheimer's disease in some families, as well as ablation/rescue genetics in mice, suggest that point mutations in the presenilin‐1 (PS1) gene can cause disease through an unknown gain‐of‐function. While mutations associated with familial Alzheimer's can alter apoptotic rates and β‐amyloid precursor processing, it is possible that other physiological effects contribute to pathogenesis. We have begun to explore effects on neurotransmission by monitoring responses of the neuropotent Ntera‐2 cell line expressing wild‐type PS1 or a FAD mutant thereof. Although no differences were initially apparent in calcium responses of metabotropic receptors, responses to glutamate were dampened in cells expressing the L286V mutant of PS1. Analysis of ionotropic agonists demonstrated that AMPA receptor alterations were responsible for this effect, whereas NMDA responses were unaltered. These data suggest that PS1 mutation could lead to cognitive deficits through subtoxic physiological effects. J. Neurosci. Res. 57:962–967, 1999. © 1999 Wiley‐Liss, Inc.