Tau mRNA 3′UTR-to-CDS ratio is increased in Alzheimer disease

Neurons frequently show an imbalance in expression of the 3′ untranslated region (3′UTR) relative to the coding DNA sequence (CDS) region of mature messenger RNAs (mRNA). The ratio varies among different cells or parts of the brain. The Map2 protein levels per cell depend on the 3′UTR-to-CDS ratio rather than the total mRNA amount, which suggests powerful regulation of protein expression by 3′UTR sequences. Here we found that MAPT (the microtubule-associated protein tau gene) 3′UTR levels are particularly high with respect to other genes; indeed, the 3′UTR-to-CDS ratio of MAPT is balanced in healthy brain in mouse and human. The tau protein accumulates in Alzheimer diseased brain. We nonetheless observed that the levels of RNA encoding MAPT/tau were diminished in these patients' brains. To explain this apparently contradictory result, we studied MAPT mRNA stoichiometry in coding and non-coding regions, and found that the 3′UTR-to-CDS ratio was higher in the hippocampus of Alzheimer disease patients, with higher tau protein but lower total mRNA levels. Our data indicate that changes in the 3′UTR-to-CDS ratio have a regulatory role in the disease. Future research should thus consider not only mRNA levels, but also the ratios between coding and non-coding regions.