Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitatinglong-term potentiation

Mutant human presenilin-1 (PS1) causes an Alzheimer's-related phenotype in the brain of transgenic mice in combination with mutant human amyloid precu rsor protein by means of increased production of amyloid peptides (Dewachte r, I., Van Dorpe, J., Smeijers, L., Gilis, M., Kuiperi, C., Laenen, I., Cal uwaerts, N., Moechars, D., Checler, F., Vanderstichele, H. & Van Leuven, F. (2000) J. Neurosci. 20, 6452-6458) that aggravate plaques and cerebrovascu lar amyloid (Van Dorpe, J., Smeijers, L., Dewachter, I., Nuyens, D., Spitta els, K., van den Haute, C., Mercken, M., Moechars, D., Laenen, I., Kuiperi, C., Bruynseels, K., Tesseur, I., Loos, R., Vanderstichele, H., Checler, F. , Sciot, R. & Van Leuven, F. (2000) J. Am. Pathol. 157, 1283-1298). This ga in of function of mutant PS1 is approached here in three paradigms that rel ate to glutamate neurotransmission. Mutant but not wild-type human PS1 (i) lowered the excitotoxic threshold for kainic acid in vivo, (ii) facilitated hippocampal long-term potentiation in brain slices, and (iii) increased gl utamate-induced intracellular calcium levels in isolated neurons. Prominent higher calcium responses were triggered by thapsigargin and bradykinin, in dicating that mutant PS modulates the dynamic release and storage of calciu m ions in the endoplasmatic reticulum. In reaction to glutamate, overfilled Ca2+ stores resulted in higher than normal cytosolic Ca2+ levels, explaini ng the facilitated long-term potentiation and enhanced excitotoxicity. The lowered excitotoxic threshold for kainic acid was also observed in mice tra nsgenic for mutant human PS2[N141I] and was prevented by dantrolene, an inh ibitor of Ca2+ release from the endoplasmic reticulum.