Tau and GSK-3β are critical contributors to α-synuclein-mediated post-stroke brain damage

doi:10.21203/rs.3.rs-2106108/v1

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Tau and GSK-3β are critical contributors to α-synuclein-mediated post-stroke brain damage

https://doi.org/10.21203/rs.3.rs-2106108/v1

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Post-stroke secondary brain damage is significantly influenced by the induction and accumulation of α-Synuclein (α-Syn). α-Syn positive inclusions are often present in tauopathies and elevated Tau levels and phosphorylation promotes neurodegeneration. Glycogen synthase kinase 3β (GSK-3β) is a known promoter of Tau phosphorylation. We currently evaluated the interaction of α-Syn with GSK-3β and Tau in post-ischemic mouse brain. Transient focal ischemia led to increased cerebral protein-protein interaction of α-Syn with both GSK-3β and Tau, and elevated Tau phosphorylation. Treatment with a GSK-3β inhibitor prevented post-stroke Tau phosphorylation. Furthermore, α-Syn interaction was observed to be crucial for post-stroke GSK-3β-dependent Tau hyperphosphorylation as it was not seen in α-Syn knockout mice. Furthermore, Tau knockout mice show significantly smaller brain damage after transient focal ischemia. Overall, the present study indicates that GSK-3β catalyzes the α-Syn-dependent Tau phosphorylation and preventing this interaction is crucial to limit the post-stroke secondary brain damage.

Focal ischemia

interaction

hyperphosphorylation

brain damage

neuroprotection

α-Synuclein (α-Syn) is one of the abundant proteins in the brain that is known to cause synucleinopathies and chronic neurodegeneration (Lashuel et al. 2013; Clinton et al. 2010; Savica et al. 2013). It is highly induced in both human and rodent brains following stroke (Kim et al. 2016; Kim et al. 2018). The accumulation and aggregation of α-Syn promote ischemic brain damage, whereas its deletion, silencing, or inhibition decreases infarction, mitochondrial fragmentation, oxidative stress, apoptosis, and autophagy and better sensorimotor and cognitive recovery after transient focal ischemia in rodents (Kim et al. 2016; Kim et al. 2018; Unal-Cevik et al. 2011). α-Syn positive inclusions are frequently observed in Tauopathies and increased Tau levels and phosphorylation are known to occur in Parkinson’s disease (Moussaud et al. 2014). This indicates that α-Syn and Tau promote each other's fibrillization and solubility indicating a synergistic mechanism of secondary brain damage (Clinton et al. 2010; Postina 2008). In CNS, both α-Syn and Tau are predominately induced in neurons (Kim et al. 2016; Pluta et al. 2018).

Tau plays a crucial role in protecting microtubule integrity that is essential for vesicular transport, polarity, and signal transduction in axons and dendrites (Chen and Jiang 2019). However, Tau phosphorylation leads to its aggregation and formation of neurofibrillary tangles that promote apoptosis after cerebral ischemia (Wen et al. 2007; Morioka et al. 2006; Gordon-Krajcer et al. 2007). Tau phosphorylation exacerbates and its deficiency protects the post-stroke rodent brain (Bi et al. 2017). Glycogen synthase kinase 3β (GSK-3β) promotes Tau hyperphosphorylation andhence its inhibition reduces brain damage and improves neurologic function after focal ischemia (Toral-Rios et al. 2020; Wang et al. 2017; Wang et al. 2016). We presently evaluated if α-Syn and GSK-3β interactively modulate Tau phosphorylation and the downstream brain damage after transient focal ischemia in adult mice.

All the procedures using animals were approved by the University of Wisconsin Research Animal Resources and Care Committee, conducted in compliance with the “Animal Research: Reporting of In Vivo Experiments (ARRIVE)” guidelines and cared in accordance with the Guide for the Care and Use of Laboratory Animals, U.S. Department of Health and Human Services Publication Number. 86 − 23 (revised) (Percie du Sert et al. 2020). Animals were randomly divided into experimental groups. The outcome measures were evaluated by an investigator blinded to study groups.

Focal ischemia

Adult, male, C57BL/6J, C57BL/6N-Snca tm1Mjff/J (SNCA knockout; α-Syn^−/−) and B6.129X1-Mapttm1Hnd/J (Tau knockout; Tau^−/−) and corresponding wild-type controls (12 weeks, 27 ± 2 g,) were obtained from Jackson Labs USA. Transient focal ischemia was induced by intraluminal middle cerebral artery occlusion (MCAO) using silicon-coated monofilament (6 − 0, Doccol Corporation USA) under isoflurane anesthesia followed by 12h or 24h of reperfusion (Chelluboina et al. 2021; Chokkalla et al. 2019; Kim et al. 2016; Kim et al. 2018; Mehta et al. 2017; Mehta et al. 2022; Kim et al. 2021). Sham-operated animals were used as control. The body temperature during surgery was maintained at 37.0 ± 0.5°C with a heating blanket. Regional cerebral blood flow (rCBF) and physiological parameters (pH, PaO₂, PaCO₂, hemoglobin, and blood glucose) were monitored. For the inclusion and exclusion criteria, mice subjected to transient MCAO that showed no signs of neurologic deficits during reperfusion or those that showed signs of hemorrhage during imaging or after euthanasia were excluded (Kim et al. 2018).

GSK-3β inhibitor administration

A cell-permeable GSK-3β Inhibitor VIII, CAS 487021-52-3 (Cat # 361549; Calbiochem USA) that regulates the biological activity of GSK-3β by phosphorylation and dephosphorylation at different residues and prevents Tau phosphorylation at a GSK-3β-specific site was injected (4 mg/kg dissolved in 5 mg/ml of DMSO and supplemented with 0.9% sterile NaCl; IV) at 30 min of reperfusion following transient MCAO. Mice in the control group received an equal volume of vehicle (Venna et al. 2015).

Co-immunoprecipitation (Co-IP): The protein-protein interaction between α-Syn, Tau, and GSK-3β was analyzed using Co-IP Assay (Cat. # ab206996; Abcam USA) as described previously (Kim et al. 2021). Briefly, the ipsilateral peri-infarct cortex was homogenized in a non-denaturing lysis buffer containing a cocktail of protease and phosphatase inhibitors. The homogenate was centrifuged (10,000g; 5 min at 4°C) and 300 µg protein equivalent of the supernatant was incubated overnight at 4°C with antibodies against α-Syn or GSK-3β (each at 1:50; Cell Signaling Technology USA) and with 25 µl of protein A/G Sepharose beads slurry (1h at 4°C). The precipitated protein complex was eluted, washed in buffer, incubated (5 min at 80°C) with NuPAGE LDS Sample Buffer (Cat. # NP0008; Life Technologies USA) and immunoblotted to evaluate the protein-protein interaction. Rabbit IgG was used as a control.

Western blotting: Ipsilateral peri-infarct cortex was homogenized in T-PER Tissue Protein Extraction Reagent (Cat. # 78510; Life Technologies USA) supplemented with a cocktail of protease and phosphatase inhibitors. Homogenates were centrifuged (10,000g for 10 min at 4°C) and 40 µg protein equivalents were electrophoresed, transferred to nitrocellulose membranes, and probed with antibodies against α-Syn, Tau, p-Tau, GSK-3β, p-GSK-3β (S9) and GAPDH (each at 1:1,000; Cell Signaling Technology USA), followed by HRP-conjugated (1:3,000) or IRDye Infrared Fluorescent Dye-conjugated (1:20,000; LI-COR) anti-rabbit or anti-mouse antibodies. Protein bands were detected using enhanced chemiluminescence or scanned with a NIR spectrum (between 680 and 800 nm) using a Li-COR Odyssey analyzer and the band intensity was quantitated with Image Studio software (LI-COR Biotechnology USA).

Infarct volume assessment

Infarct size was assessed with T2-MRI (4.7T small animal system scanner; Agilent Technologies USA). Briefly, mice were anesthetized with isoflurane and 8–10 coronal brain slices at 1.0 mm thickness and 20 × 20 mm² fields were scanned under isoflurane anesthesia as described previously (Chelluboina et al. 2021). The respiration rate was monitored during the imaging. The Infarct size was computed blindly, and total infarct volume was configured by numeric integration of data from serial coronal sections factoring-in sectional intervals and corrected for edema using NIH ImageJ software with an FDF plugin as described before (Chelluboina et al. 2021; Kim et al. 2018; Mehta et al. 2022; Mehta et al. 2015).

Transient focal ischemia induced phosphorylation of GSK-3β and Tau

The p-Tau levels increased (by 2 to 2.5 fold; p < 0.05) and p-GSK-3β levels decreased (by 3 to 4 fold; p < 0.05) in the ipsilateral peri-infarct cortex at 6h, 12h and 24h of reperfusion following transient MCAO in adult mice compared with sham (Fig. 1A and B). Whereas, protein levels of total Tau and total GSK-3β were unaltered at any reperfusion period tested compared with sham (Fig. 1A and B).

α-Syn forms a complex with p-Tau and p-GSK-3β after focal ischemia: We previously demonstrated that induction of α-Syn after focal ischemia in rodents increases DRP1 phosphorylation that promotes mitochondrial fragmentation (Kim et al. 2016). To understand if α-Syn promotes GSK-3β phosphorylation and the further downstream Tau hyperphosphorylation that modulates DRP1 and mitochondrial damage after focal ischemia, we immunoprecipitated protein complex with α-Syn antibodies and evaluated the interaction of α-Syn with p-Tau, and p-GSK-3β at 12h reperfusion following transient MCAO in the ipsilateral cerebral cortex. As expected, α-Syn protein levels increased significantly in the post-ischemic brain (Fig. 2A). α-Syn binding to p-Tau increased and to p-GSK-3β decreased significantly after transient MCAO compared to sham (Fig. 2A). Whereas, α-Syn binding to total Tau and total GSK-3β were not altered after transient MCAO (Fig. 2A).

Using α-Syn^−/− mice, we investigated if post-ischemic GSK-3β activation and Tau hyperphosphorylation are α-Syn dependent. In α-Syn^−/− mouse brain, total GSK-3β and total Tau protein levels didn’t change following transient MCAO and 12h of reperfusion in the ipsilateral cortex compared to sham (Fig. 2B). This is similar to what we observed in wild-type mice. However, α-Syn deletion prevented post-ischemic Tau hyperphosphorylation seen in wild-type mice (Fig. 2B). We further evaluated the interaction of α-Syn, Tau, and GSK-3β following immunoprecipitation with GSK-3β antibody. In α-Syn^−/− mice subjected to transient MCAO and 12h reperfusion, both GSK-3β phosphorylation and Tau phosphorylation were similar to sham (Fig. 2B), unlike in wild-type control. This indicates that GSK-3β bound to Tau is S9 phosphorylated (inactive), which can’t prevent Tau phosphorylation in the wild-type mice when it was decreased following transient MCAO. However, in α-Syn^−/− mice, reversal of GSK-3β phosphorylation prevents Tau hyperphosphorylation. This suggests that α-Syn availability is essential for GSK-3β suppression and the resulting Tau hyperphosphorylation in the post-ischemic brain.

Inhibition of GSK-3β prevented Tau hyperphosphorylation in the ischemic brain

We injected mice with a potent GSK-3 inhibitor VIII that prevents Tau phosphorylation at a GSK-3-specific site to confirm the role of GSK-3β in controlling Tau hyperphosphorylation (Venna et al. 2015). GSK-3β inhibitor given IV at 30 min of reperfusion significantly reversed the decrease in GSK-3β S9 phosphorylation and subsequently decreased Tau phosphorylation at 12h of reperfusion following transient MCAO compared to the vehicle control group (Fig. 3). This confirms that GSK-3β mediates Tau phosphorylation after focal ischemia.

Tau deletion decreased brain damage after transient focal ischemia

We previously demonstrated that mice lacking α-Syn suffered less brain damage and recovered motor functions after focal ischemia better than wild-type mice. As shown above, α-Syn seems to influence GSK-3β and its downstream Tau signaling. As Tau hyperphosphorylation and its aggregation are known to promote neurodegeneration (Ballatore et al. 2007), we tested the effect of focal ischemia in Tau^−/− mice. Tau^−/− mice showed no total Tau or p-Tau protein after transient MCAO or sham surgery (Fig. 4A). Tau^−/− mice showed significantly smaller infarct volume (by 38%; p < 0.05) at 1 day of reperfusion following 1h of transient MCAO compared with Tau^+/+ mice (Fig. 4B).

We previously reported that post-ischemic induction and accumulation of α-Syn significantly contributes to post-ischemic brain damage (Kim et al. 2016). Previous studies showed that Tau and GSK-3β are also promoters of secondary brain damage after focal ischemia (Bi et al. 2017; Venna et al. 2015). Both α-Syn and Tau cause synucleinopathies and Tauopathies associated with neurodegenerative disorders (Ballatore et al. 2007; Galpern and Lang 2006; Savica et al. 2013). Clinical studies indicate a substantial correlation between these abnormalities with the co-occurrence of α-Syn and Tau inclusions (Savica et al. 2013; Galpern and Lang 2006; Forman et al. 2002).

GSK-3β is a major kinase that hyperphosphorylates Tau leading to its accumulation and Tauopathies (Credle et al. 2015; Duka et al. 2009; Lei et al. 2011). Transgenic mice overexpressing GSK-3β showed Tau hyperphosphorylation and hippocampal neuronal death (Wang et al. 2017). Whereas inhibiting GSK-3β enhanced synaptic and cognitive capabilities in Alzheimer's disease mouse models and reduced infarct volume and BBB disruption and enhanced cognitive recovery after stroke (Farr et al. 2014; Zhou et al. 2022; Wang et al. 2017; Venna et al. 2015).

The current studies show that the basal levels of GSK-3β and Tau are unaltered after focal ischemia, but their phosphorylation status changes significantly. Importantly, GSK-3β S9 phosphorylation is reduced, leading to its activation and downstream Tau phosphorylation. The key component that enables this seems to be the increased post-ischemic expression of α-Syn, which binds to both GSK-3β and Tau. Previous studies showed that α-Syn is directly involved in Tau hyperphosphorylation (Duka et al. 2006). Our studies confirm this by showing that post-ischemic Tau phosphorylation doesn’t change in α-Syn knockout mice (known to be protected after focal ischemia) compared to sham indicating that α-Syn binding is critical. GSK-3β activity is inhibited when the S9 residue is phosphorylated (Duka et al. 2009). Our studies show that the GSK-3β inhibitor promoted S9 phosphorylation and prevented the downstream Tau phosphorylation. This indicates the essentiality of GSK-3β in Tau phosphorylation and an association between α-Syn, GSK-3β and Tau in mediating post-ischemic brain damage.

Tau is a neuron-specific cytoskeletal protein involved in the assembly and stabilization of microtubules regulating axonal transport and maintaining neuronal morphology (Guo et al. 2017). Progressive hyperphosphorylation leads to its aggregation/deposition, impairing normal cellular functions and leading to excitotoxicity, whereas lowering Tau is neuroprotective (Roberson et al. 2007). The present study shows that Tau knockout mice that lack total Tau as well as p-Tau show significantly lower infarction following transient focal ischemia. Since Tau protein regulates synaptic function, Tau deletion or knockdown in mice could lower brain-derived neurotrophic factor, leading to deficiencies in long-term depression and long-term hippocampal potentiation in aging (Gonçalves et al. 2020; Velazquez et al. 2018). Our studies also indicate a progression from α-Syn to GSK-3β to Tau in post-ischemic brain damage.

Overall, the current study demonstrates that a complex formed by α-Syn, Tau, and GSK-3β is necessary for GSK-3β-catalyzed Tau hyperphosphorylation in the post-stroke brain and that α-Syn serves as a key initiator of Tau-mediated ischemic brain damage. Disrupting these interactions might be a novel strategy to prevent post-stroke brain damage.

ACKNOWLEDGMENTS

Partially supported by NIH RO1 NS101960 and UW Department of Neurological Surgery. Dr. Vemuganti is the recipient of a Research Career Scientist award (# IK6BX005690) from the US Department of Veterans Affairs. We thank Mr. Shreyas Kumar for proofreading the text.

AUTHOR CONTRIBUTIONS

SLM, THK, BC and RV contributed to the conception and design of the study; SLM, THK, and BC contributed to the acquisition and analysis of data; SLM, BC, and RV contributed to drafting the text.

COMPETING INTEREST

The authors declare that they have no competing interests.

Data and materials availability

All data needed to evaluate the conclusions in the paper are present in the main document.

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Tau and GSK-3β are critical contributors to α-synuclein-mediated post-stroke brain damage

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