Molecular cloning and characterization of a cDNA encoding the cerebrovascular and the neuritic plaque amyloid peptides.

TLDR

Deposits of amyloid fibers are abundant in the walls of blood vessels and in neuritic plaques in the brains of patients with Alzheimer disease and adults with Down syndrome. The authors synthesized oligonucleotide probes from the amyloid peptide sequence to screen a human brain cDNA library for the gene encoding this peptide. A 1.7‑kb cDNA clone encoding a 412‑amino‑acid protein that includes the 28‑aa amyloid peptide was identified, with a 3.3‑kb mRNA expressed in Alzheimer’s, Down syndrome, and control brains; homologous genes in several mammals and localization to human chromosome 21 indicate evolutionary conservation and a potential genetic link between Alzheimer’s disease and Down syndrome.

Abstract

Deposits of amyloid fibers are found in large numbers in the walls of blood vessels and in neuritic plaques in the brains of patients with Alzheimer disease and adults with Down syndrome. We used the amino acid sequence of the amyloid peptide to synthesize oligonucleotide probes specific for the gene encoding this peptide. When a human brain cDNA library was screened with this probe, a clone was found with a 1.7-kilobase insert that contains a long open reading frame coding for 412 amino acid residues including the 28 amino acids of the amyloid peptide. RNA gel blots revealed that a 3.3-kilobase mRNA species was present in the brains of individuals with Alzheimer disease, with Down syndrome, or with no apparent neurological disorders. Southern blots showed that homologous genes are present in the genomic DNA of humans, rabbits, sheep, hamsters, and mice, suggesting that this gene has been conserved through mammalian evolution. Localization of the corresponding genomic sequences on human chromosome 21 suggests a genetic relationship between Alzheimer disease and Down syndrome, and it may explain the early appearance of large numbers of neuritic plaques in adult Down syndrome patients.