Differential enrichment of simple sequence repeats in selected Alzheimer-associated genes

The involvement of beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD) has been well documented. In addition, a significant degree of information has been documented regarding the genetics of Abeta production and aggregation in familial forms of AD (FADs). However, the information regarding the causes or mechanism(s) responsible for Abeta accumulation in non-FADs is not as extensive and requires further elucidation. Simple sequence repeat (SSR)-mediated molecular misreading has recently been implicated in Abeta accumulation, via neuronal expression of mutant forms of the Abeta precursor (APP+1) and ubiquitin-B (UBB+1) proteins. Also, additional studies have demonstrated that the enrichment or representation of SSRs correlates with the rate of such molecular misreading. Therefore, we have analyzed the representation of SSRs in the DNA sequences of selected AD genes (ADGs) and non-ADGs. SSRs of various motifs were found to be differentially enriched in both ADGs and non-ADGs. More importantly, all known AD-associated SSRs (ADSSRs) were found to be highly enriched in the APP and UBB genes. Since molecular misreading is believed to be a widespread phenomenon during aging, the high enrichment of ADSSRs in the APP and UBB genes suggests that older individuals may exhibit relatively high rates of neuronal expression of mutant APP+1 and UBB+1 peptides. This is consistent with the proposed involvement of these peptides in the pathogenesis of non-FADs.