AGE-RELATED PHOSPHORYLATION AND FRAGMENTATION EVENTS INFLUENCE THE DISTRIBUTION PROFILES OF DISTINCT TAU-ISOFORM IN MOUSE-BRAIN

Native tau isoforms were analyzed in adult mouse brain to determine wh ether they are differentially distributed and to identify molecular al terations that modify individual isoforms in an age-dependent manner. In general, the distribution profiles of 42-50 kDa tau were distinct f rom those of larger, hyperphosphorylated species of 55-69 kDa. The hip pocampus and neocortex had concentrated levels of 55 kDa tau, and mode rate amounts of 62-69 kDa isoforms. The latter species were similarly expressed in thalamic and hindbrain tissue; however, the noncortical r egions were uniquely enriched in high molecular weight tau (97-110 kDa ). When assessing hippocampal tau across age, increasing levels of 69 kDa tau were found to correlate with a gradual reduction in 42-50 kDa isoforms. Endogenous phosphatase activity induced an opposite correlat ion, thus supporting the idea that certain isoform conversions that oc cur with age stem from hyperphosphorylation. Age-related increases in 69 and 97 kDa tau also corresponded to enhanced levels of tau29, a put ative tau fragment that exhibited an atypical localization (concentrat ed in olfactory bulb and hindbrain samples). These findings indicate t hat phosphorylation and fragmentation events influence tau distributio n patterns, and that the former modification may promote the latter. T hey also raise the possibility that brain regions targeted by Alzheime r disease are distinguished by distinct tau profiles.