Intron-exon swapping of transglutaminase mRNA and neuronal tau aggregationin Alzheimer's disease

In order to understand the mechanism for insoluble neurotoxic protein polym erization in Alzheimer's disease (AD) brain neurons, we examined protein an d gene expression for transglutaminase (TGase 2; tissue transglutaminase (t TG)) in hippocampus and isocortex. We found co-localization of tTG protein and activity with tau-positive neurofibrillary tangles, whereas mRNA and se quence analysis indicated an absolute increase in tTG; synthesized. Althoug h apoptosis in AD hippocampus is now an established mode of neuronal cell d eath, no definite underlying mechanism(s) is known. Since TGase-mediated pr otein aggregation is implicated in polyglutamine ((CAG)(n)/Q(n) expansion) disorder apoptosis, and expanded Q(n) repeats are excellent TGase substrate s, a role for TG;ase in AD is possible. However, despite such suggestions a lmost 20 years ago, the molecular mechanism remained elusive. We now presen t one possible molecular mechanism for tTG-mediated, neurotoxic protein pol ymerization leading to neuronal apoptosis in AD that involves not its subst rates (like Q(n) repeats) but rather the unique presence of alternative tra nscripts of tTG; mRNA In addition to a full-length (L) isoform in aged non- demented brains, we found a short isoform (S) lacking a binding domain in a ll AD brains. Our current results identify intron-exon "switching" between L and S isoforms, implicating G-protein-coupled signaling pathways associat ed with tTG that may help to determine the dual roles of this enzyme in neu ronal life and death processes.