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Astrocyte tau deposition in progressive supranuclear palsy is associated with dysregulation of MAPT transcription
Acta Neuropathologica Communications volume 12, Article number: 132 (2024)
Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by 4R tau deposition in neurons as well as in astrocytes and oligodendrocytes. While astrocytic tau deposits are rarely observed in normal aging (so-called aging-related tau astrogliopathy, ARTAG) and Alzheimer’s disease (AD), astrocytic tau in the form of tufted astrocytes is a pathognomonic hallmark of PSP. Classical biochemical experiments emphasized tau synthesis in neurons in the central nervous system, suggesting that astrocytic tau inclusions might be derived from uptake of extracellular neuronal-derived tau. However, recent single-nucleus RNAseq experiments highlight the fact that MAPT, the gene encoding tau, is also expressed by astrocytes, albeit in lower amounts. We, therefore, revisited the question of whether astrocyte-driven expression of tau might contribute to astrocytic tau aggregates in PSP by performing fluorescent in situ hybridization/immunohistochemical co-localization in human postmortem brain specimens from individuals with PSP and AD with ARTAG as well as normal controls. We find that, in PSP but not in AD, tau-immunoreactive astrocytes have higher levels of MAPT mRNA compared to astrocytes that do not have tau aggregates. These results suggest that astrocytic responses in PSP are unique to this tauopathy and support the possibility that fundamental changes in PSP astrocyte-endogenous mRNA biology contribute to increased synthesis of tau protein and underlies the formation of the astrocytic tau deposits characteristic of PSP.
Introduction
Progressive supranuclear palsy (PSP) is one of a number of neurogenerative tauopathies distinguished from each other by unique neuropathological features and hallmarks [15, 16]. Although all the primary tauopathies are characterized by hyperphosphorylation and aggregation of the cytoskeletal protein tau, these diseases differ from each other in the regional distribution, cell type, morphology, and structure of these aggregates. Arguably, fundamental differences in underlying tau biology underscore these disease-specific characteristics and translate into the distinct clinical phenotypes associated with each of these diseases.
Tau protein is encoded by the MAPT gene, which contains a number of splice sites leading to tau isoforms of different lengths. Inclusion of exon 10 encodes four repeat (4R) tau which contains a fourth microtubule binding domain and generates a protein critically different from the three repeat (3R) tau variant lacking that extra microtubule binding repeat motif [2, 11].
Biochemically, the tau aggregates in PSP mainly contain 4R tau [2, 11, 12, 26] while anatomically, tau aggregates in astrocytes are pathognomonic of PSP although tau inclusions are also found in neurons, predominantly in the brainstem and motor-related subcortical structures [15, 16]. By contrast, in Alzheimer’s disease (AD) tau deposits contain a mixture of 3R and 4R tau, occur primarily in limbic and cortical structures, and are predominantly neuronal, although occasional astrocytic tau inclusions can be observed—collectively termed age-related tau astrogliopathy (ARTAG) [12, 16]. The morphology of tau-containing astrocytes is also distinctive, with tufted astrocytes defining PSP and thorn-shaped astrocytes being the main morphology in ARTAG [13]. Since astrocytic tau inclusions have been observed to correlate with synaptic alterations in PSP and corticobasal degeneration (CBD) and synaptic changes are amongst the earliest drivers of altered/failing function in neurodegenerative disease, the importance of understanding the origin and functional impact of astrocytic inclusions is of high interest.
Why tau accumulates in distinct cell types in the various tauopathies remains unknown. Tau is considered a member of the metastable subproteome—a set of highly expressed and aggregation-prone proteins whose normal function relies on a delicate equilibrium between gene expression levels and homeostasis of the cellular proteostasis systems [3, 17]. Therefore, one possibility is that an increased MAPT gene expression within astrocytes is a major driver of tau accumulation in PSP tufted astrocytes. Indeed, the idea that tau expression might be related to the development of neuropathology in PSP is supported by several lines of evidence. Polymorphisms in the MAPT gene are linked to enhanced neuropathological changes, especially oligodendroglial coiled bodies and tufted astrocytes [12]. In particular, the H1 haplotype of MAPT is associated with a predisposition to develop PSP [4, 10]. Previous work in mouse models has shown that overexpression of human MAPT in astrocytes is sufficient to induce tau pathology reminiscent of PSP in these cells [5, 7]. Recent human PSP single-nucleus RNA-sequencing (snRNA-seq) datasets show that the MAPT gene is expressed in the central nervous system primarily in neurons, but that glia—especially astrocytes—do show readily detectable levels of MAPT mRNA [28]. We reasoned that astrocytes that develop inclusions in PSP either have a unique ability to take up and accumulate tau from the extracellular environment or, plausibly, begin to overexpress the MAPT gene in response to as yet unidentified triggers, leading to enhanced synthesis of the tau protein beyond their clearance capacity, resulting in the development of the pathognomonic tau inclusions.
To begin to test which of these potential mechanisms underlies astrocytic tau accumulation in PSP we developed methods to perform fluorescent in situ hybridization and concurrent immunohistochemistry to allow spatial resolution of MAPT mRNA transcripts in human postmortem brain tissue. We compared individuals with PSP and AD with ARTAG, and asked if astrocyte (or neuronal) MAPT mRNA levels are increased in the subset of neurons or astrocytes that develop tau inclusions relative to those that do not. We observed an increase in MAPT mRNA specifically in astrocytes containing tau inclusions in PSP, but not in AD with ARTAG, suggesting the possibility that a dysregulation of tau gene expression contributes to the accumulation of tau in the tufted astrocytes characteristic of PSP.
Materials and methods
Brain donors
Frozen samples and 7 μm-thick formalin-fixed paraffin-embedded (FFPE) sections from the striatum and frontal association cortex of age- and sex-balanced 10 PSP, 9 AD, and 5 normal controls were obtained from the Massachusetts Alzheimer’s Disease Research Center (MADRC) Neuropathology Core brain bank. PSP donors met current neuropathological diagnostic criteria for PSP [23]. AD donors met current clinical and neuropathological diagnostic criteria for AD [18] but were selected to have astrocytic tau inclusions consistent with ARTAG [14, 20]. Normal control donors did not have any clinical symptoms of any neurodegenerative disease during life and did not meet neuropathological diagnostic criteria for any neurodegenerative disease at autopsy examination. All donors or their next-of-kin provided informed written consent for the brain donation, which was conducted under the MADRC Neuropathology Core Institutional Review Board protocol. Approximatively, 0.5 g of frozen frontal cortex or striatum were dissected and kept at − 80 °C until processing. Case information is in Table 1.
Immunohistochemistry with peroxidase-DAB
We performed automated immunohistochemistry (IHC) for phospho-Tau (Ser202, Thr205) antibody (clone AT8, ThermoFisher Scientific #MN1020, 1:2,000) in FFPE sections from the striatum and frontal cortex with the peroxidase-3,3′-diaminobenzidine (DAB) method using a Leica BOND Polymer Refine Detection kit (Leica Biosystems, DS9800) in a Leica BOND RX Fully Automated Research Stainer (Leica Biosystems). Immunostained sections were then scanned in a VS-120 Olympus slide scanner under the 40x objective.
Fluorescence in situ hybridization assay
RNAScope
We performed the RNAScope protocol using the RNAscope multiplex fluorescent assay v2 kit (ACD #323100) and following the manufacturer instructions for frozen tissue. Briefly, brains were cut on a cryostat to a thickness of 8 μm and then mounted onto Superfrost slides (Fisher Scientific) with three sections per slide. Sections were immersed in 4% paraformaldehyde at 4 °C for 15 min and then dehydrated through increasing ethanol gradient. Slides were then allowed to dry at room temperature (RT) and sections were outlined with a hydrophobic pen. Samples were then exposed to RNAScope Hydrogen Peroxide solution (ACD #322335) for 10 min at RT followed by a 5-minute incubation in RNAScope protease IV (ACD #322340).
Sections were then incubated with probes for 2 h at 40 °C. The following probes were used in different combinations and were run alongside a negative control probe (ACD #320871) and a positive control probe Hs-UBC (ACD #310041). SLC1A2 was used as a marker of astrocytes while SYP was used as a marker for neurons.
Combination 1: Hs-MAPT (ACD #408991) and Hs-SLC1A2-C3 (ACD #444721-C3).
Combination 2: Hs-MAPT (ACD #408991) and Hs-SYP-C3 (ACD #311421-C3).
Combination 3: Hs-MAPT (ACD #408991), Hs-MAPT-AS1-C2 (ACD # 564491-C2), and Hs-SLC1A2-C3 (ACD #444721-C3).
Combination 4: Hs-MAPT (ACD #408991), Hs-MAPT-AS1-C2 (ACD # 564491-C2), and Hs-SYP-C3 (ACD #311421-C3).
Following probe incubation, consecutive amplification steps were performed in the same oven using the RNAScope Multiplex FL v2 kit. C1 probes were developed using TSA Plus Cy3 (Akoya Biosciences, #NEL744E001KT), C3 probes with TSA Plus Fluorescein (Akoya Biosciences, #NEL741001KT), and C2 probes (when applicable) with TSA Plus Cy5 (Akoya Biosciences, #NEL745E001KT).
Autofluorescence quenching
Immediately following the final step of RNAScope kit the sections were washed 3 times in tris-buffered saline (TBS). To quench tissue autofluorescence, sections were then incubated in 1x TrueBlack (Biotium 23007) in 70% ethanol for 30 s at RT before immediately being washed 3 times in TBS. Sections were never allowed to dry out and were processed in small batches to minimize tissue autofluorescence.
RNA quality control
For all slides, a positive control probe for UBC (encoding ubiquitin C) was run on an adjacent section and used to determine RNA integrity with strict cut-offs. Because RNA integrity varied between brain regions and was lost over time following sectioning, slides which failed this quality control test were not processed for further analysis (Table 1 shows details of which donors were used for each analysis).
Fluorescent immunohistochemistry
The samples were then processed for an IHC assay using the monoclonal mouse phospho-Tau (Ser202, Thr205) antibody (clone AT8, ThermoFisher Scientific #MN1020). Briefly samples were blocked in 5% Normal Donkey Serum (NDS) for 1 h at RT followed by overnight incubation with AT8 antibody (1:500) in 2.5% NDS in TBS. Sections were washed and then incubated with donkey anti-mouse IgG Alexa Fluor 750 (Abcam AB175738) 1:200) in 2.5% NDS in TBS for 1 h at RT. Sections were then washed and counterstained with 1:1,000 DAPI in TBS for 5 min and mounted using Immu-Mount (Fisher Scientific, 9990402). Immunostained sections were scanned in a VS-120 Olympus slide scanner with the 40x objective for all relevant channels.
QuPath image analyses
Images were loaded directly into QuPath open access image analysis software [1] and areas of grey matter were outlined manually. Positive cell detection was used on all annotated areas detecting nuclei using the DAPI channel allowing split by shape. Cell expansion was set at 5 μm and the cell outlines included the cell nucleus. Astrocytes and neurons were identified in the FITC channel by their SLC1A2 and SYP expression, respectively, since C3 probes were visualized with TSA Plus Fluorescein. A single threshold of mean FITC staining in the nucleus was used per image to delineate astrocytes or neurons as appropriate. Although this number differed on a donor-by-donor basis depending on background and staining integrity, the experimenter assigning this threshold was blind to diagnosis and only FITC and DAPI channels were used in the determination of an appropriate cut-off.
Subcellular detection was used to quantify the number of transcripts for MAPT and MAPT-AS1 [24]. The expected mean spot size was 1µm2 (range 0.5-2.0µm2). When two spots or more spots were clustered together they were split first by intensity and then by size to achieve the appropriate number of transcripts. Again, exact detection thresholds varied depending on background and signal intensity but were decided by a blinded experimenter using only the relevant channel. A case-wise cut-off value for AT8 signal intensity were variably applied but was again determined by a blinded investigator.
Statistical analyses
GraphPad Prism v10.0.2 (Dotmatics, Boston, MA) was used for all statistical analyses and graphs. Mean transcript number per case was determined for astrocyte and neurons in the different brain regions for all cells that were either AT8- or AT8+. For donors with less than ten AT8 + cells this value was excluded although the AT8- value was still used for statistics. Individual donors are summarized by a single average data point and graphs show mean +/- SD unless otherwise indicated. Histograms were generated using cells from all cases for each designation as indicated on the graph and are binned as indicated. Repeated measures mixed effect model was used to determine an effect of AT8 positivity on MAPT and MAPT-AS1 transcript number with disease state as the row effect and AT8 status as the column effect. Uncorrected Fisher’s LSD was used as a post-hoc test for these analyses. The same test was used to assess SLC1A2 intensity in astrocytes. Ratios were analyzed using a one-tail t-test or one-way ANOVA against a theoretical mean of 1 (a ratio of 1 indicating no difference between AT8- and AT8+).
Results
We utilized RNAscope, an in situ hybridization technique which allows for highly specific single transcript detection with excellent spatial resolution, in postmortem brain tissue collected from control, AD with ARTAG, and PSP individuals (Table 1 and Supplemental Fig. S1) [27]. Probes used were designed for MAPT (all tau isoforms) as well as SLC1A2 (encoding the astrocyte-specific glutamate transporter EAAT2/GLT-1) and SYP (encoding the neuron-specific synaptophysin) (Fig. 1A) [29]. We found a robust number of MAPT transcripts in both the nucleus and cytoplasm of astrocytes in all three conditions. Using the positive cell detection method on QuPath, cells were identified based on DAPI staining, then expanded by 5 μm, and then marked as astrocytes or neurons depending on the intensity of the RNA marker for each of those cell types (i.e., SLC1A2 vs. SYP respectively), [1]. We then quantified the number of MAPT transcripts in those cells using the subcellular detection method. Quantification showed a significantly higher number of MAPT transcripts in neurons vs. astrocytes (p < 0.0001, F (3, 71) = 68.64); the number of MAPT transcripts per astrocyte was ~ 30–50% relative to that of neurons and higher in astrocytes from striatum than frontal cortex (FC) (p = 0.0280) (Fig. 1B). The transcript number did not seem to be affected by diagnosis (p = 0.2380) (Fig. 1D). Interestingly, there were twice as many astrocytes with > 5 transcripts of MAPT in striatum vs. FC (~70% vs. ~35%), revealing regional differences that may contribute to selective vulnerability to tau aggregation (Fig. 1C).
In PSP, astrocyte tau pathology can precede neuronal tau pathology in some brain regions, including specifically in the striatum [16]. Therefore, we asked if striatal astrocytes in which MAPT expression is higher than average might be the same astrocytes bearing tau pathology before any such neuronal pathology is seen. To investigate this, we combined RNAscope for MAPT and SLC1A2 probes with IHC for the phospho-tau epitope AT8 (Fig. 2A) and classified astrocytes into AT8 + and AT8- depending on their AT8 staining intensity. We found significantly more MAPT transcripts in AT8 + vs. AT8- astrocytes in PSP but not in AD with ARTAG donors (Interaction factor F (2, 9) = 5.129, PSP AT8 + vs. PSP AT8- p = 0.0012) (Fig. 2B). AT8 + astrocytes in PSP had on average 50% more MAPT transcripts when compared with AT8- astrocytes from the same donor, whereas AT8 + astrocytes did not show this difference in AD with ARTAG donors—although these had substantially fewer AT8 + astrocytes than PSP donors (t = 4.187, df = 5, p = 0.0086) (Fig. 2C). This increase in MAPT transcripts in AT8 + astrocytes in PSP donors was driven by a dramatic increase in the proportion of cells with a high number of MAPT transcripts (Fig. 2D). For example, only 5% of astrocytes in the control donors had more than 23 MAPT transcripts while over 20% of AT8 + PSP astrocytes had more than 23 MAPT transcripts (Supplemental Fig. S2A).
We also examined astrocytes in the frontal cortex and found a similar phenomenon (Fig. 3A). In PSP donors, AT8 + astrocytes were found to have on average 50% more MAPT transcripts compared to AT8- astrocytes from the same donors (Interaction factor F (2, 9) = 7.962, PSP AT8 + vs. PSP AT8- p = 0.0036) (Fig. 3B, C). However, this difference appeared to be driven by a smaller number of astrocytes with very high MAPT transcript levels (Fig. 3D, Supplemental Fig. S2B) and FC astrocytes appeared to make less MAPT overall.
Importantly there was no difference in the intensity of SLC1A2 staining across the groups indicating that this increase in MAPT transcript level is due neither to a general increase in all mRNA transcripts in AT8 + astrocytes nor to a technical artifact whereby AT8 + astrocytes were better stained or imaged (Supplemental Fig. S3A). Crucially, when we quantified the intensity of MAPT probe staining, PSP astrocytes designated as AT8 + had significantly higher MAPT intensity when compared with AT8- intensity from that same donor (Supplemental Fig. S3B), further reinforcing our conclusions.
Previous reports have shown no increase in MAPT levels in neurons with tau inclusions in AD [21]. To investigate if this increase in MAPT transcripts in PSP astrocytes was specific to astrocytes or also occurred in tangle-bearing neurons, we used RNAscope to probe for MAPT and SYP (as a marker of neurons) followed by IHC for AT8 (Fig. 4A). In agreement with this previous report, we saw no difference in MAPT transcript levels in AT8 + neurons compared to AT8- neurons in AD with ARTAG donors. Here we have extended this finding to PSP as we observed no increased in MAPT transcript level in AT8 + vs. AT8- neurons in either striatum or FC of PSP donors (Fig. 4B, C).
MAPT-AS1 is a recently discovered naturally occurring antisense oligonucleotide that has been postulated to impact the expression of MAPT potentially leading to neurodegenerative phenotypes [25]. To assess if MAPT-AS1 dysregulation could be driving this increase in MAPT transcript levels in AT8 + astrocytes from PSP donors we used RNAscope to probe for MAPT-AS1 and MAPT alongside either SYP (for neurons) or SLC1A2 (for astrocytes) followed by IHC with AT8 (Fig. 5A). We found significantly more MAPT-AS1 transcripts (mixed model, p = 0.0030) in neurons than in astrocytes, the majority of which had no MAPT-AS1 at all, however there was no association between MAPT-AS1 transcript number and AT8 immunoreactivity in any of the three conditions (Fig. 5B-C).
Discussion
Recent snRNA-seq studies suggest that dysregulation of transcriptional activity is correlated with tau deposition [22, 28]. We reasoned that this mechanism could lead to enhanced MAPT gene expression in astrocytes and, subsequently, higher chance of tau deposition (i.e., tufted astrocytes). Thus, we performed in situ hybridization and concurrent IHC to explore the possibility that MAPT gene expression would be disrupted in tufted astrocytes in PSP. We found that in PSP brains, astrocytes bearing tau pathology expressed more MAPT than astrocytes lacking tau pathology. As a control for both a nonspecific feature of reactive astrocytes and for a closely related but independent tauopathy, we explored MAPT expression in selected AD brains which also had tau positive astrocytes (ARTAG) [20]. Interestingly, we found that in AD astrocytes with tau pathology there was no such increase in MAPT expression, suggesting different mechanisms of astrocytic tau accumulation in these two tauopathies (i.e., increased transcription and synthesis vs. uptake from extracellular space). Regarding neurons, we saw no change in MAPT expression in AT8 + vs. AT8- neurons in either PSP or AD, implying different mechanisms of astrocytic vs. neuronal tau accumulation in PSP.
Substantial upregulation of MAPT in a subset of PSP astrocytes correlated with the presence of phosphorylated tau in these cells. This does not appear to reflect technical issues with measuring mRNA in these cells, as we found no significant relationship between MAPT-AS1 and MAPT transcript number in neurons or astrocytes in these cases. Intriguingly, a recent snRNA-seq dataset has shown an impact of H1/H2 haplotype on the expression of MAPT in astrocytes [9], and the H1 haplotype is strongly associated with propensity to develop PSP. While it is an interesting possibility that this haplotype may contribute to the altered MAPT expression observed in our PSP donors, the current study was not sufficiently powered to examine the effect of the H1/H2 haplotype.
Two recent studies have examined astrocyte MAPT expression in PSP. In the first, Fiock et al. using human inducible pluripotent stem cells (hiPSc)-derived astrocytes reported a preferential uptake of 4R compared to 3R recombinant tau [6], suggesting another reason for the accumulation of 4R tau in astrocytes. This study also performed an analysis similar to ours, using in situ hybridization for MAPT combined with GFAP and AT8 IHC to determine tau positive and tau negative astrocytes in PSP brain donors. Four individuals were studied, with an average of over 3,000 astrocytes/donor, and no difference in MAPT expression was observed between PSP astrocytes that contained tau protein inclusions and those that did not. The reason for the discrepancy between Fiock et al.’s data and the current study is not clear, but we note that only ~ 50% of astrocytes in their study had detectable MAPT mRNA, while snRNA-seq data suggest that essentially all astrocytes express MAPT [8], raising the possibility of lower detection sensitivity. In the second recent study, Forrest et al. used RNAScope in situ hybridization combined with AT8 IHC to explore MAPT expression in neurons, oligodendroglia, and astrocytes in three control and three PSP donors [8]. In accord with the current results, FC tufted astrocytes contained statistically significantly more MAPT mRNA than non-tau containing astrocytes in two of the three PSP donors, and the third donor appeared to have quantitatively more MAPT mRNA as well, although the pooled astrocyte results did not reach statistical significance [8]. Moreover, one of the three donors did have statistically significantly higher expression of MAPT in tufted astrocytes vs. non-tau containing astrocytes in the basal ganglia. Interestingly, in the same study, MAPT expression was significantly higher in coiled body-containing oligodendroglia than in tau-negative oligodendroglia, indicating a similar mechanism in these two glial cell types [8]. Here we have used a much larger cohort of donors with robust quality controls for RNA integrity to expand upon these data and confirm that tufted astrocytes in PSP show an increase in MAPT expression while thorn-shaped astrocytes typical of ARTAG in AD do not, indicating different mechanisms of astrocytic tau accumulation in these two diseases.
Taken together, the current data support the idea that a dysregulation of MAPT expression occurs in tufted astrocytes that accumulate tau aggregates in PSP. Whether this reflects astrocyte-specific stress responses in PSP, unique genetic risk factors associated with MAPT expression that correlate with the risk to develop PSP, or astrocyte-neuron interactions specific to the neurodegenerative environment associated with PSP remains uncertain, but the observations presented here suggest that altered astrocytic MAPT expression is a key feature of the molecular biology underpinning disease progression in PSP and should be considered in the context of potential pathologic molecular “drivers” and “ensconces” of disease progression in this tauopathy. Moreover, our findings lend support to the therapeutic approach of lowering MAPT expression in PSP with antisense oligonucleotides [19].
Data availability
The datasets during and/or analyzed during the current study available from the corresponding author upon reasonable request.
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Acknowledgements
This work was supported by a sponsored research agreement from Bristol Myers Squibb to Massachusetts General Hospital, by the Harrison Gardner, Jr. Innovation Award (AS-P), and by NIH P30AG062421 (BTH) and a grant from the Rainwater foundation (BTH).
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RJJ, LS, and BTH conceptualized the study; AM, RJJ, and DPF sectioned brains and performed ISH and IHC; RJJ performed imaging acquisition and analysis; RJJ performed data analysis; RJJ, AS-P, LS and BTH wrote the manuscript, BTH secured the funding.
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Dr. Hyman has a family member who works at Novartis and owns stock in Novartis; he serves on the SAB of Dewpoint and of Latus, and owns stock. He serves on a scientific advisory board or is a consultant for AbbVie, Ambagon, Aprinoia Therapeutics, Arvinas, Avrobio, Biogen, BMS, Cure Alz Fund, Cell Signaling, Dewpoint, Latus, Novartis, Sofinnova, Vigil, Violet, Voyager, WaveBreak. His laboratory is supported by research grants from the National Institutes of Health, Cure Alzheimer’s Fund, Tau Consortium, and the JPB Foundation – and sponsored research agreements from Abbvie, BMS, and Biogen. Dr. Shinobu is an employee of Bristol Myers Squibb (BMS) and owns stock in BMS and Voyager Tx. Dr. Serrano-Pozo has a material transfer agreement with Ionis Pharmaceuticals, Inc. to use antisense oligonucleotides in mouse models of AD.
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Jackson, R.J., Melloni, A., Fykstra, D.P. et al. Astrocyte tau deposition in progressive supranuclear palsy is associated with dysregulation of MAPT transcription. acta neuropathol commun 12, 132 (2024). https://doi.org/10.1186/s40478-024-01844-6
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DOI: https://doi.org/10.1186/s40478-024-01844-6