Hypersensitivity to seizures in beta-amyloid precursor protein deficient mice.
Secreted forms of the beta-amyloid precursor protein (beta-APP) have neuroprotective properties in vitro and may be involved in the containment of neuronal excitation. To test whether loss of secreted forms of beta-APP (sAPPs) may enhance excitotoxic responses, we injected mice homozygous for a targeted mutation of the beta-APP gene (beta-APPDelta/Delta) intraperitoneally with kainic acid. We found that in these mice, kainic acid induced seizures initiated earlier, and acute mortality was enhanced compared to isogenic wild-type mice independently from the callosal agenesis phenotype observed to occur at increased frequency in APP mutant mice. Expression of c-fos in cortex and cingulate gyrus was enhanced in beta-APPDelta/Delta mice, although the amount of structural damage and apoptosis in the hippocampal pyramidal cell layer and cortex was similar to that of controls. When cerebellar granule cell cultures and cortical neuronal cultures were challenged with glutamate receptor agonists, the rates of cell death and apoptosis of beta-APPDelta/Delta mice were indistinguishable from those of controls. Therefore, deficiency of sAPPs causes facilitation of seizure activity in the absence of enhanced cell death. Since enhanced seizures were observed also in mice homozygous for a deletion of the entire beta-APP gene, this phenotype results from a loss of APP rather than from a dominant effect of APPDelta.
Steinbach
J P
JP
Institute of Neuropathology, University Hospital, Zurich, Switzerland.
Müller
U
U
Leist
M
M
Li
Z W
ZW
Nicotera
P
P
Aguzzi
A
A
D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D003561:Cytarabine / Q000494:pharmacology; D003643:Death; D005091:Exons; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*
D016564:Amyloid beta-Protein Precursor; D016760:Proto-Oncogene Proteins c-fos; D003561:Cytarabine; D007608:Kainic Acid