Abstract
Spleen tyrosine kinase (SYK) plays a major role in inflammation and in adaptive immune responses and could therefore contribute to the neuroinflammation observed in various neurodegenerative diseases. Indeed, previously we have reported that SYK also regulates β-amyloid (Aβ) production and hyperphosphorylation of Tau protein involved in these diseases. Moreover, SYK hyperactivation occurs in a subset of activated microglia, in dystrophic neurites surrounding Aβ deposits, and in neurons affected by Tau pathology both in individuals with Alzheimer's disease (AD) and in AD mouse models. SYK activation increases Tau phosphorylation and accumulation, suggesting that SYK could be an attractive target for treating AD. However, the mechanism by which SYK affects Tau pathology is not clear. In this study, using cell biology and biochemical approaches, along with immunoprecipitation and immunoblotting, quantitative RT-PCR, and ELISAs, we found that SYK inhibition increases autophagic Tau degradation without impacting Tau production. Using neuron-like SH-SY5Y cells, we demonstrate that SYK acts upstream of the mammalian target of rapamycin (mTOR) pathway and that pharmacological inhibition or knockdown of SYK decreases mTOR pathway activation and increases autophagic Tau degradation. Interestingly, chronic SYK inhibition in a tauopathy mouse model profoundly reduced Tau accumulation, neuroinflammation, neuronal and synaptic loss, and also reversed defective autophagy. Our results further suggest that the SYK up-regulation observed in the brains of individuals with AD contributes to defective autophagic clearance leading to the accumulation of pathogenic Tau species. These findings further highlight SYK as a therapeutic target for the treatment of tauopathies and other neurodegenerative proteinopathies associated with defective autophagic clearance.
Highlights
Spleen tyrosine kinase (SYK) plays a major role in inflammation and in adaptive immune responses and could contribute to the neuroinflammation observed in various neurodegenerative diseases
As Tau clearance is known to be regulated via autophagy, we investigated the possible impact of SYK inhibition on the mammalian target of rapamycin (mTOR) pathway and autophagic degradation of Tau in SH-SY5Y cells
We show that SYK inhibition with BAY61-3606 results in decreased total Tau, p-AKT, p-S6 kinase (S6K), and p-mTOR levels in differentiated SH-SY5Y cells (Fig. S1B), confirming the data obtained with undifferentiated SH-SY5Y cells
Summary
Our previous data suggest that SYK may regulate Tau clearance since we have observed that SYK up-regulation promotes Tau accumulation without affecting Tau expression [26]. A trend for an increase in total Tau levels was observed following 24 h of treatment with the mTOR activator MHY1485, which was prevented by SYK inhibition (Fig. 2, C and D) showing that SYK inhibition can overcome the effects of a stimulation of the mTOR pathway. The increased degradation of t-Tau following the co-treatment with CQ and the SYK inhibitor compared with CQ alone (Fig. 3) suggests that SYK inhibition increases autophagy initiation but may increase the lysosomal degradation of Tau, which was antagonized by CQ
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