Clearance of seed‐dependent tau aggregation by lithium‐induced autophagy: Implications of strain‐specificity

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Tau protein aggregation is the major constituent of Alzheimer’s disease (AD) neurofibrillary tangles. Lithium, act as a drug to treat bipolar disorders, has been shown to have various neuroprotective effects including promoting autophagy and acting as an inhibitor of major tau kinase GSK‐3. Our laboratory previously reported that lithium treatment decreased the amount of insoluble tau and motor disturbance with increased LC3‐II positive puncta in tau transgenic mice (Neurobiol Dis, 2012.46). Here, we sought to examine whether lithium influences tau aggregation in different tauopathy via autophagy promotion using a seed‐dependent cell model.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>SH‐SY5Y cells were transfected by C‐terminal tau fragment, Tau‐CTF24 (243‐441), and introduced AD and other tauopathy brain seeds (Progressive supranuclear palsy [PSP], Corticobasal degeneration [CBD]). After 48‐hours LiCl treatments, sarkosyl‐insoluble fractions were prepared. For Transmission Electron Microscopy (TEM), cells were cultured on 35 mm dishes and stained with 2% OsO<jats:sub>4</jats:sub>. Double labeled cells harboring GFP‐CTF24 and mCherry‐LC3 were established.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Cells expressing Tau‐CTF24 exposed to AD seeds exhibited a profoundly decreased amount of insoluble tau accompanied with LC3‐II elevation upon treatment with 10 mM LiCl for 2 days. Electron microscopic analysis demonstrated the increase of multilamellar bodies and autophagic vacuoles (AVs). Therapeutic concentration of LiCl (0.2 ‐ 1.0 mM) also demonstrated decreased propensity of insoluble tau in a dose‐dependent manner. The number of puncta stained with both GFP‐CTF24 and mCherry‐LC3 were observed only in LiCl‐treated cell soma. An autophagy inhibitor, 3‐Methyladenine (3‐MA), antagonized LiCl effect. One of IMPase inhinbitor (L690, 330) decreased insoluble tau in cell models and subsequently decreased activity as well as elevated AVs, which mimics LiCl effcts Interestingly, the LiCl effect on insoluble tau reduction was much smaller in CBD than in AD, although reduction of aggregation by PSP is comparable with AD.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>These results suggest that aggregated tau protein is degraded by LiCl‐induced autophagy in a strain‐specific manner, implying that the mechanism might include IMPase signaling cascade.</jats:p></jats:sec>