Molecular evolution of τ protein: Implications for Alzheimer's disease

The brains of patients with Alzheimer's disease contain deposits of hyperphosphorylated τ proteins that have polymerized into insoluble fibrils. These deposits, in neurofibrillary tangles and dystrophic neurites, correlate with loss of cells and synapses, and consequently with dementia. Neurofibrillary pathology occurs in humans, as well as certain ungulates, including goats, sheep, and cows, but not in nonhuman primates. We hypothesize that the differences among species in the propensity to develop neurofibrillary pathology may be attributable to variations in the amino acid sequence of τ proteins. To investigate this hypothesis, we sequenced τ- encoding mRNA transcripts from the brains of rhesus monkey and domesticated goat and compared them with the known sequences of τ mRNAs from humans. The major difference we observed was that some τ mRNAs from rhesus monkey neocortex contain exon 8, whereas this exon has not been found in cortical τ from human or goat. Cows express very low levels of exon 8, and they tend to develop sparse neurofibrillary pathology with aging. We also found a transcribed T-related pseudogene in rhesus monkey, which may be present in humans. We propose that differences in the expression of τ and τ-related protein sequences may underlie the predilection of human but not monkey brains to develop neurofibrillary degeneration.