Fred van Leeuwen and his research group presented new data regarding their molecular misreading hypothesis for sporadic AD (Abstract 107.7). The molecular misreading hypothesis suggests that the inaccurate conversion of genomic information into mRNA and subsequent translation of nonsense proteins, particularly as a result of dinucleotide deletions, may be a causative event in sporadic AD. The authors examined immunoreactivity for antibodies directed against the APP+1 frameshift mutation in the brains of cognitively impaired and cognitively normal individuals with Down's syndrome as a model of the early stages of the progression of AD pathology, and reported that immunoreactivity for APP+1 is present in the absence of other neuropathological indicators, including neurofibrillary tangles and Aß deposition, in nondemented DS cases. This suggests that dinucleotide deletions in APP transcripts are an early event in AD pathogenesis, not merely a result of other pathogenic processes.
This data may conflict with published findings demonstrating immunoreactivity for Aß deposition in nondemented DS individuals as young as their teens (van Leeuwen did not detect Aß within their young DS cases). However, a complete comparison of these markers will yield additional insight in the future. These data represent a preliminary step in evaluating the potential of these missense mutations to cause neurofibrillary tangle formation, the accumulation of Aß, or other neuropathological events characteristic of AD neurodegeneration. These data add to the interesting hypothesis of molecular misreading in sporadic AD.
In other work presented at the SFN meeting, van Leeuwen's group reported evidence that the same mutant RNAs detected in AD and DS brain can be detected in human neuronal cell lines, suggesting that the aberrant synthesis of missense proteins may be a common event in highly transcriptionally active cells. In current work, Dr. van Leeuwen is developing a transgenic model overexpressing these missense mutants to further address the molecular misreading hypothesis.—Aileen J. Anderson
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