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Letters to Nature
Nature 331, 530 - 532 (11 February 1988); doi:10.1038/331530a0

Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity

Nobuya Kitaguchi, Yasuyuki Takahashi, Yasuo Tokushima, Satoshi Shiojiri & Hirataka Ito

Bio-Science Laboratory, Life Science Research Laboratories, Asahi Chemical Industry Co. Ltd., 2-1 Samejima, Fuji-Shi, Shizuoka 416, Japan

Alzheimer's disease1 is characterized by cerebral deposits of amyloid β-protein (AP) as senile plaque core and vascular amyloid2–6, and a complementary DNA encoding a precursor of this protein (APP) has been cloned from human brain7–11. From a cDNA library of a human glioblastoma cell line, we have isolated a cDNA identical to that previously reported, together with a new cDNA which contains a 225-nucleotide insert. The sequence of the 56 a mi no acids at the N-terminal of the protein deduced from this insert is highly homologous to the basic trypsin inhibitor family12, and the lysate from COS-1 cells transfected with the longer APP cDNA showed an increased inhibition of trypsin activity. Partial sequencing of the genomic DNA encoding APP showed that the 225 nucleotides are located in two exons. At least three messenger RNA species, apparently transcribed from a single APP gene by alternative splicing, were found in human brain. We suggest that protease inhibition by the longer APP(s) could be related to aberrant APP catabolism.

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