Homology of the amyloid beta protein precursor in monkey and human supports a primate model for beta amyloidosis in Alzheimer's disease.
Progressive cerebral deposition of the amyloid beta-protein (A beta P) occurs in Alzheimer's disease and during aging of certain mammals (eg, human, monkey, dog) but not others (eg, mouse, rat). The authors cloned and sequenced a full-length cDNA encoding the beta-protein precursor (beta APP) of cynomolgus monkey. The predicted amino acid sequence of the 695-residue protein is completely homologous to that of human. The alternatively transcribed exons encoding the Kunitz protease inhibitor region in monkey were cloned, showing only a single conservative amino acid substitution in the 751-residue form of beta APP and four substitutions in beta APP770. Immunoblots of cerebral cortex with antibodies to various beta APP domains showed highly similar beta APP polypeptides in human and monkey, in contrast to those of mouse and rat. The latter differences reflect sequence substitutions, transcriptional regulation, and possibly post-translational modifications that may decrease the amyloidogenic potential of rodent beta APP. Immunocytochemistry of aged cynomolgus brain showed A beta P deposited in blood vessels and diffuse and compacted plaques closely resembling those of humans, and the presence of beta-amyloid-associated proteins (alpha 1-antichymotrypsin; complements C1q and C3c) characteristic of A beta P deposits in Alzheimer's disease. The authors' findings demonstrate that cynomolgus monkey and perhaps other primates provide a close animal model for examining the early transcriptional and post-translational processing of beta APP that precedes A beta P deposition during aging and in Alzheimer's disease.
Podlisny
M B
MB
Department of Neurology (Neuroscience), Harvard Medical School, Boston, Massachusetts.
Tolan
D R
DR
Selkoe
D J
DJ
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000235:genetics*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor; D000686:Amyloidosis / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D004586:Electrophoresis; D005091:Exons; D006801:Humans; D007150:Immunohistochemistry; D008252:Macaca fascicularis / Q000097:blood / Q000235:genetics*; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D012377:Rodentia / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011498:Protein Precursors; D004247:DNA