Mutant presenilins disturb neuronal calcium homeostasis in the brain of transgenic mice, decreasing the threshold for excitotoxicity and facilitating long-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 precursor protein by means of increased production of amyloid peptides (Dewachter, I., Van Dorpe, J., Smeijers, L., Gilis, M., Kuiperi, C., Laenen, I., Caluwaerts, N., Moechars, D., Checler, F., Vanderstichele, H. & Van Leuven, F. (2000) J. Neurosci. 20, 6452-6458) that aggravate plaques and cerebrovascular amyloid (Van Dorpe, J., Smeijers, L., Dewachter, I., Nuyens, D., Spittaels, K., van den Haute, C., Mercken, M., Moechars, D., Laenen, I., Kuipéri, C., Bruynseels, K., Tesseur, I., Loos, R., Vanderstichele, H., Checler, F., Sciot, R. & Van Leuven, F. (2000) J. Am. Pathol. 157, 1283-1298). This gain of function of mutant PS1 is approached here in three paradigms that relate 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 glutamate-induced intracellular calcium levels in isolated neurons. Prominent higher calcium responses were triggered by thapsigargin and bradykinin, indicating that mutant PS modulates the dynamic release and storage of calcium ions in the endoplasmatic reticulum. In reaction to glutamate, overfilled Ca(2+) stores resulted in higher than normal cytosolic Ca(2+) levels, explaining the facilitated long-term potentiation and enhanced excitotoxicity. The lowered excitotoxic threshold for kainic acid was also observed in mice transgenic for mutant human PS2[N141I] and was prevented by dantrolene, an inhibitor of Ca(2+) release from the endoplasmic reticulum.
Schneider
I
I
Department of Neuropathology, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
Reverse
D
D
Dewachter
I
I
Ris
L
L
Caluwaerts
N
N
Kuiperi
C
C
Gilis
M
M
Geerts
H
H
Kretzschmar
H
H
Godaux
E
E
Moechars
D
D
Van Leuven
F
F
Herms
J
J
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D053764:Presenilin-1
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D001920:Bradykinin; D007608:Kainic Acid; D002118:Calcium