Cytotoxic Fragment of Amyloid Precursor Protein Accumulates in Hippocampus after Global Forebrain Ischemia

We developed an antibody specific to β-amyloid precursor protein (βAPP) fragments possessing the exact amino terminus of the β-amyloid peptide and examined its induction in postischemic hippocampus. In control hippocampus, this APP fragment was lightly observed in pyramidal neurons of CA sectors and dentate granule cells. Transient forebrain ischemia enhanced accumulation of the APP fragment in CA1 pyramidal neurons. Seven days after the ischemia, while the APP fragment was still observed in dentate granule cells and CA3 neurons, it disappeared in dead CA1 neurons. While astrocytes did not show in any immunoreactivity throughout the experiment, those in the CA1 sector showed moderate immunoreactivity 7 days after the ischemia. The APP fragment has a cytotoxic effect on cultured neurons. These results suggest that the accumulation of the cytotoxic APP fragment in CA1 neurons may play a role in the development of delayed neuronal death after the ischemic insult.

[1]  D. Mann,et al.  Dominant and differential deposition of distinct β-amyloid peptide species, Aβ N3(pE), in senile plaques , 1995, Neuron.

[2]  J. Peterson,et al.  The immunohistochemical distribution of protein kinase C isozymes is altered in the canine brain and basilar artery after subarachnoid hemorrhage , 1994, Neuroscience Letters.

[3]  J. Kimura,et al.  Temporal Profiles of Accumulation of Amyloid β/A4 Protein Precursor in the Gerbil after Graded Ischemic Stress , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[4]  Y. Ihara,et al.  Spatial resolution of the primary beta-amyloidogenic process induced in postischemic hippocampus. , 1994, The Journal of biological chemistry.

[5]  Mark P. Mattson,et al.  β-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer's disease , 1993, Trends in Neurosciences.

[6]  D. Selkoe.  Physiological production of the β-amyloid protein and the mechanism of Alzheimer's disease , 1993, Trends in Neurosciences.

[7]  M. Mullan,et al.  Genetics and molecular advances in Alzheimer's disease , 1993, Trends in Neurosciences.

[8]  Carl W. Cotman,et al.  Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[9]  M. Mattson,et al.  Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the β-amyloid precursor protein , 1993, Neuron.

[10]  L. Thal,et al.  Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide , 1993, Nature.

[11]  R. Schmidt-Kastner,et al.  Selective vulnerability of the hippocampus in brain ischemia , 1991, Neuroscience.

[12]  D. Kirschner,et al.  Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. , 1990, Science.

[13]  K. Yoshikawa,et al.  Formation of amyloid-like fibrils in COS cells overexpressing part of the Alzheimer amyloid protein precursor , 1990, Nature.

[14]  G. Heinrich.  Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease. , 1989, The New England journal of medicine.

[15]  Takaaki Kirino,et al.  Delayed neuronal death in the gerbil hippocampus following ischemia , 1982, Brain Research.

[16]  F. Crawford,et al.  Genetic and molecular advances in Alzheimer's disease. , 1993, Trends in neurosciences.

[17]  K. Yoshikawa.  Neurotoxicity of β-amyloid , 1993, Nature.

[18]  K. Suzuki,et al.  Autolytic transition of mu-calpain upon activation as resolved by antibodies distinguishing between the pre- and post-autolysis forms. , 1992, Journal of biochemistry.

[19]  C. Cotman,et al.  In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. , 1991, Brain research.