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Pathologic Thr175 Tau Phosphorylation in CTE and CTE with ALS

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Pathologic Thr175 Tau Phosphorylation in CTE and CTE with ALS Published Ahead of Print on January 3, 2018 as 10.1212/WNL.0000000000004899 ARTICLE OPEN ACCESS Pathologic Thr175 tau phosphorylation in CTE and CTE with ALS Alexander J. Moszczynski, PhD, Wendy Strong, BSc, Kathy Xu, MSc, Ann McKee, MD, Arthur Brown, PhD, Correspondence and Michael J. Strong, MD Dr. M.J. Strong [email protected] Neurology® 2018;90:e1-8. doi:10.1212/WNL.0000000000004899 Abstract Objective To investigate whether chronic traumatic encephalopathy (CTE) and CTE with amyotrophic lateral sclerosis (CTE-ALS) exhibit features previously observed in other tauopathies of pathologic phosphorylation of microtubule-associated protein tau at Thr175 (pThr175 tau) and Thr231 (pThr231 tau), and glycogen synthase kinase–3β (GSK3β) activation, and whether these pathologic features are a consequence of traumatic brain injury (TBI). Methods Tau isoform expression was assayed by western blot in 6 stage III CTE cases. We also used immunohistochemistry to analyze 5 cases each of CTE, CTE-ALS, and 5 controls for ex- pression of activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau within spinal cord tissue and hippocampus. Using a rat model of moderate TBI, we assessed tau pathology and phospho-GSK3β expression at 3 months postinjury. Results CTE and CTE-ALS are characterized by the presence of all 6 tau isoforms in both soluble and insoluble tau isolates. Activated GSK3β, pThr175 tau, pThr231 tau, and oligomerized tau protein expression was observed in hippocampal neurons and spinal motor neurons. We observed tau neuronal pathology (fibrillar inclusions and axonal damage) and increased levels of pThr175 tau and activated GSK3β in moderate TBI rats. Conclusions Pathologic phosphorylation of tau at Thr175 and Thr231 and activation of GSK3β are features of the tauopathy of CTE and CTE-ALS. These features can be replicated in an animal model of moderate TBI. From the Molecular Medicine Research Group, Robarts Research Institute (A.J.M., W.S., K.X., A.B., M.J.S.), and Department of Clinical Neurological Sciences (M.J.S.), Schulich School of Medicine & Dentistry, Western University, Canada; and VA Boston Healthcare System, Boston University Alzheimer’s Disease and CTE Center (A.M.), Boston University School of Medicine, MA. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by the NHLPA Challenge Fund. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. e1 Glossary AD = Alzheimer disease; ALS = amyotrophic lateral sclerosis; ALSci = amyotrophic lateral sclerosis with cognitive impairment; ANOVA = analysis of variance; CTE = chronic traumatic encephalopathy; GSK3β = glycogen synthase kinase–3β; NFT = neurofibrillary tangle; pGSK3β = phospho–glycogen synthase kinase–3β; pThr175 tau = tau phosphorylated at threonine 175; pThr231 tau = tau phosphorylated at threonine 231; RT = room temperature; TBI = traumatic brain injury. Chronic traumatic encephalopathy (CTE) is a fatal neu- approved by the University of Western Ontario Animal Care rodegenerative disease that is closely associated with Committee in accordance with the Canadian Council on traumatic brain injury (TBI).1 Although TBI is typically Animal Care. associated with elite athletes, it also occurs as a result of both recreational and non-sport-related accidents.2,3 While CTE and CTE-ALS studies there remains some controversy, a relationship between Microscope slides with 6-μm-thick hippocampal and spinal TBI and amyotrophic lateral sclerosis (ALS) has been ob- cord sections from neuropathologically confirmed cases of served, with between 4% and 6% of patients with CTE CTE (n = 5) and CTE-ALS (n = 5) in addition to 5 control demonstrating either clinical or neuropathologic features cases with no neuropathologic evidence of a neurodegen- – consistent with a diagnosis of ALS.4 7 CTE is an affective, erative disease state (cases 7–19) were used for immuno- behavioral, or cognitive disorder associated with repetitive histochemical studies. An additional 6 cases (cases 1–6) head trauma that has a characteristic pattern of widespread were obtained as frozen tissue from anterior cingulate and neuronal and glial microtubule-associated tau (tau protein) temporal pole. All tissue and slides were obtained from the deposition.8 In patients with concomitant ALS (CTE- Veterans Affairs–Boston University–Concussion Legacy ALS), motor neuron degeneration is also observed, in- Foundation brain bank and were neuropathologically 8,18 cluding the presence of TDP-43 neuronal cytoplasmic diagnosed as stage III CTE. Demographicdataare inclusions.9 summarized in table e-1 (http://links.lww.com/ WNL/A99). The presence of a tauopathy in CTE and CTE-ALS raises the potential of a shared pathophysiology with ALS with cog- Tau fractionation and western blot nitive impairment (ALSci), where tau is pathologically Tau protein was isolated from the anterior cingulate gyrus and phosphorylated at threonine 175 (pThr175 tau) and threo- the temporal pole of 6 stage III CTE cases and a single Alz- nine 231 (pThr231 tau), yielding pathogenic tau oligomers heimer disease (AD) case as a control. Tau isolation, frac- that subsequently assemble into insoluble pathologic tau tionation, dephosphorylation, and western blot were fi 1,10–15 175 conducted as previously reported (e-Methods, http://links. brils. In this process, pThr tau induces phosphor- 19,20 ylation and activation of glycogen synthase kinase–3β lww.com/WNL/A100). (GSK3β), which in turn promotes tau phosphorylation at Thr231.16 Supporting the key role of pThr175, pThr175 tau has After transfer to nitrocellulose membranes, samples were only been observed in pathologic states, including a broad probed for total tau with rabbit anti-tau T14/T46 antibodies range of tauopathies.10,13,17 (Thermo-Fisher, Burlington, Canada). After horseradish peroxidase–conjugated secondary antibody labeling, blots To date, there have been no detailed studies of the phos- were visualized using enhanced chemiluminescence (Perkin- phorylation state of tau in either CTE or CTE-ALS. Given Elmer, Waltham, MA). this, we examined postmortem archival tissues from patients with CTE and patients with CTE-ALS for pThr175, Immunohistochemistry pThr 231, the active isoform of GSK3β (phospho-GSK3β Six-micrometer paraffin-embedded sections from the hippo- [pGSK3β]), and tau oligomerization. We also examined campus and spinal cord were analyzed for all cases. Immu- whether this process can be triggered by moderate TBI in nohistochemistry was conducted using a series of antibodies arodent. (complete details in table e-2, http://links.lww.com/WNL/ A99) that recognized pThr175 tau (21st Century, Marlboro, MA), pThr231 tau (Thermo-Fisher), and oligomeric tau (T22; Methods EMD Millipore, Billerica, CA), and activated GSK3β (pTyr216; BD Biosciences, Mississauga, Canada). Antigen Standard protocol approvals, registrations, retrieval (10 mM sodium citrate, 0.05% Tween 20 pH 6.0) and patient consents was conducted for all antibodies using a pressure cooker All studies on human tissues were conducted in accordance (2100 Retriever; Aptum Biologics, Southampton, UK, table with the institutional ethics board standards at University e-2). Endogenous peroxidase was quenched with 3% hydro- Hospital (London, Canada) and Boston University School of gen peroxide (VWR, Mississauga, Canada). Primary antibody Medicine (Massachusetts). All animal protocols were incubation was performed at 4°C overnight in blocking buffer e2 Neurology | Volume 90, Number 5 | January 30, 2018 Neurology.org/N (5% bovine serum albumin, 0.3% Triton-X 100 in 1 × to reduce artefactual tau pathology.22,23 After 24 hours of phosphate-buffered saline). After washing, secondary anti- fixation, tissue was embedded in paraffin. body (1:200 biotinylated immunoglobulin G) incubation was performed for 1 hour at room temperature (RT) in blocking Western blots buffer. Immunoblots were also performed using isolates from 6 moderate TBI rats and 4 age-matched controls (e- Antigen Methods, links.lww.com/WNL/A100). Briefly, brain tis- Antibody complex was visualized with horseradish peroxi- sue was homogenized in RIPA buffer containing protease dase according to the manufacturer’sinstructions(Vec- and phosphatase inhibitors followed by concentration de- tastain ABC kit, Vector Laboratories, Burlingame, CA), termination by modified Bradford assay (Bio-Rad, Hercu- followed by substrate development with 3,39-dia- les, CA). After immunoprecipitation of brain lysate for total minobenzidine (DAB). Counterstaining was performed tau (T46 antibody), the entire immunoprecipitation yield using Harris hematoxylin. was run as a western blot (e-Methods). After transfer to nitrocellulose membrane, blots were probed with rabbit The extent of pathology was described semiquantitatively anti-pThr175 tau. Gels were stripped for 30 minutes at 50°C as previously reported using visualization with a 20× ob- and reprobed with rabbit anti–total tau (Abcam, Cam- jective under light microscopy (Olympus BX45; Center bridge,UK).pGSK3β studies were performed on total Valley,
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