Studies on the tau lysosomal proteolytic pathway

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Tau is the major component of paired helical filaments (PHF) in Alzheimer's disease (AD) brain. The presence of tau-immunoreactive, PHF-like fibrils was reported in the muscle affected by inclusion body myositis (IBM), and amorphous tau deposits were recently found in chloroquine myopathy (CM), an experimental model for IBM.We investigated CM to obtain insight into PHF formation in AD brain. In CM tau mRNA level was transiently upregulated in the early phase, while tau itself slowly accumulated in the late phase. The temporal profiles of tau mRNA levels and its accumulation were very similar to those of beta-amyloid protein precursor (APP) and its carboxyl-terminal fragments, both of which have been known to be degraded in lysosomes. Immunocytochemistry showed that tau progressively accumulated in the rimmed vacuoles with increased acid phosphatase activities, and immunoelectron microscopy demonstrated that tau was located within the vacuoles. These results suggest that tau is degraded … More in lysosomes or their functional equivalents in the muscle.To confirm the tau degradation pathway in lysosome we analyzed the autophagolysosomes from liver of the transgenic rat overexpressing the shortest form of human tau under transcriptional control of the chicken beta-actin promoter. We found that tau was present in autophagolysosomes from leupeptin-treated liver, whereas it was not detected in those from leupeptin-untreated liver. These results suggest that tau is also degraded in lysosomes in liver. The observations in both muscle and liver prompted us to search for a receptor for tau in rat brain lysosomes. Rat brain lysosomal membranes were separated by SDS polyacrylamide gel electrophoresis, transferred to nitrocellulose membrane, and incubated with tau. We found that the proteins with the molecular weight of 130, 100, and 76 kDa specifically bound tau. On the other hand, we identified MP5O (glutamate dehydrogenase) in the lysosomal fraction as a possible tau-binding protein by use of tau affinity chromatography. Less