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Wang Y, Martinez-Vicente M, Krüger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet. 2009 Nov 1;18(21):4153-70. PubMed.
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In this manuscript, Yipeng Wang and colleagues showed lysosome/macroautophagy as a new tau degradation pathway in addition to the ubiquitin/proteasome pathway. Since an aggregated form of tau is thought to be involved in neuronal loss in AD, studies on identifying toxic aggregation, and removing or inhibiting it, are important in terms of future therapy for AD. In this manuscript, insoluble tau that is formed on the membrane of lysosomes exerts cytotoxicity. The tau repeat region is first cleaved at the N-terminus by an unidentified thrombin-like protease, then at the C-terminus by cathepsin L on the lysosomal membrane. The cleaved fragment is highly amyloidogenic and forms oligomers, which are thought to be a toxic tau aggregate. The toxic tau aggregate may be degraded by macroautophagy. Therefore, inhibition of cathepsin L, and/or activation of macroautophagy could become a potential therapy for AD.
It is surprising that toxic tau oligomers form on the surface of lysosomes. The tau construct that the authors used in this study is the repeat region. It is conceivable that a small amount of toxic tau oligomers assembled by the repeat region fragments is enough to cause cellular dysfunction (neuronal toxicity), and these oligomers can seed tau aggregation (NFT formation); however, full-length hyperphosphorylated tau is still the dominant species existing in human tauopathies. We would be interested to know if full-length tau also forms toxic tau oligomers on this organelle.
We have found granular tau oligomers as an intermediate form of tau fibrils in vitro and in human brain (e.g., Sahara et al., 2008). The increased granular tau oligomer is seen in Braak stage I of prefrontal cortex, and we also observed a significant inverse correlation between oligomers and heat shock proteins (HSPs) including Hsp90, Hsp40, Hsp27, α-crystallin, and CHIP. These results suggest that granular tau oligomer formation and corresponding changes in chaperone-responsible proteolytic systems occur long before NFT formation. If the toxic oligomer reported in this study and our granular tau oligomer are the same aggregate, then the granular tau oligomer we detect may have formed on lysosomes and may be a toxic form of tau aggregate. Overall, accumulated findings suggest that the tangles themselves might not be toxic, but that intermediate species are. Therefore, we need to identify a toxic form of tau aggregate, and find ways of inhibiting tau-induced neurotoxicity as a therapy for AD.
References:
Sahara N, Maeda S, Takashima A. Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration. Curr Alzheimer Res. 2008 Dec;5(6):591-8. PubMed.
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