In patients with Alzheimer's disease or Down's syndrome, the cerebellar cor
tex exhibits protein deposits in neurofibrillary tangles and neuritic plaqu
es. Recently, the deposits have been shown to contain protein fragments of
ubiquitin-B and amyloid precursor protein (APP) with an aberrant carboxyl t
erminus resulting from frameshift mutations (dinucleotide deletions; Delta
GU or Delta GA) in or adjacent to GAGAG motifs in their mRNAs, a process re
ferred to as molecular misreading. We have now used a bacterial expression
system with the green fluorescent protein as a reporter to screen gene tran
scripts from aged controls, Alzheimer's disease, and Down's syndrome for mo
lecular misreading. Novel frameshift mutations at a number of locations in
the transcripts of the ubiquitin-B and APP genes were discovered (Delta GA,
DeltaG, Delta GU, Delta GG, Delta CA, Delta AU, DeltaA, Delta AA, DeltaC,
DeltaU, and insertion of an A). Interestingly, most mutations were in close
proximity of short simple repeats (GAGAG, GGUGGU, GAGACACACA, UCAUCAUCA, C
AAACAAA, and GAAGAAGAA), demonstrating that the GAGAG motif does not consti
tute the only hot spot for transcriptional errors. Unlike the previously de
tected aberrant APP fragments, some of the novel ones have the potential to
generate the neurotoxic peptide beta -amyloid, We conclude that during agi
ng molecular misreading is a widespread phenomenon.