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Mutation-specific neuropathologic signatures in MAPT-associated frontotemporal lobar degeneration

Bogdani, Marika, Jadhav, Vaishnavi S., Kraemer, Brian C., Grabowski, Thomas J., Jayadev, Suman, Domoto-Reilly, Kimiko, Liachko, Nicole F., Bird, Thomas D., Dirk Keene, C., Latimer, Caitlin S.·2026·Acta Neuropathologica
DOI 10.1007/s00401-026-03047-wPMC PMC13331856
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Fig. 1 Neurodegeneration in different brain regions of V337M, P301L, or L284L mutation carriers. a–c Heat map illustrating the average grade of severity of neurodegeneration in the examined brain regions (green shade) for each patient group with the indicated mutation. d–f Representative images of middle frontal gyrus (MFG) sections stained with hematoxylin, eosin, and Luxol fast blue (HEL), shown at low magnification. Among the three MAPT mutations, P301L led to the most severe cortical atrophy. g–i Representative images of MFG GM stained with HEL, shown at high magnification. Most extensive transcortical gliosis was observed in the P301L group. j–l Representative images of MFG sections stained with GFAP. m–o Representative images of MFG white matter (WM) stained with HEL. The WM integrity is better preserved in the V337M mutation group. Images are from donor 6 (d, g, j, m), donor 13 (e, h, k, n), and donor 18 (f, I, l, o). Scale bars: 1 mm (shown in d and applies to e and f), and 50 µm (shown in g and applies to h–o)
Fig. 1 Neurodegeneration in different brain regions of V337M, P301L, or L284L mutation carriers. a–c Heat map illustrating the average grade of severity of neurodegeneration in the examined brain regions (green shade) for each patient group with the indicated mutation. d–f Representative images of middle frontal gyrus (MFG) sections stained with hematoxylin, eosin, and Luxol fast blue (HEL), shown at low magnification. Among the three MAPT mutations, P301L led to the most severe cortical atrophy. g–i Representative images of MFG GM stained with HEL, shown at high magnification. Most extensive transcortical gliosis was observed in the P301L group. j–l Representative images of MFG sections stained with GFAP. m–o Representative images of MFG white matter (WM) stained with HEL. The WM integrity is better preserved in the V337M mutation group. Images are from donor 6 (d, g, j, m), donor 13 (e, h, k, n), and donor 18 (f, I, l, o). Scale bars: 1 mm (shown in d and applies to e and f), and 50 µm (shown in g and applies to h–o)CC BY-NC-ND · PubMed Central
Fig. 2 Tau burden in different brain regions of V337M, P301L, or L284L mutation carriers. a–c Heat map illustrating the average grade of tau burden in gray matter (blue shade) and white matter (yellow to red shades) in the examined brain regions for each patient group with the indicated mutation. Representative images of AT8 immunohistochemistry of tissues sections from the indicated regions: middle frontal gyrus gray matter (MFG GM, d–f), MFG white matter (WM, g–i), hippocampus (j–l), dentate fascia (DF, m–o), and substantia nigra (SN, p–r). Images are from donor 1 (d, g, j, m, p), donor 8 (e, h, k, n, q), and donor 17 (f, I, l, o, r). Scale bars: 100 µm (shown in d, g, m, p and applies to e, f, h, I, n, o, q, r), and 1 mm (shown in j and applies to k and l)
Fig. 2 Tau burden in different brain regions of V337M, P301L, or L284L mutation carriers. a–c Heat map illustrating the average grade of tau burden in gray matter (blue shade) and white matter (yellow to red shades) in the examined brain regions for each patient group with the indicated mutation. Representative images of AT8 immunohistochemistry of tissues sections from the indicated regions: middle frontal gyrus gray matter (MFG GM, d–f), MFG white matter (WM, g–i), hippocampus (j–l), dentate fascia (DF, m–o), and substantia nigra (SN, p–r). Images are from donor 1 (d, g, j, m, p), donor 8 (e, h, k, n, q), and donor 17 (f, I, l, o, r). Scale bars: 100 µm (shown in d, g, m, p and applies to e, f, h, I, n, o, q, r), and 1 mm (shown in j and applies to k and l)CC BY-NC-ND · PubMed Central
Fig. 3 Tau pathology associated with the V337M mutation. Representative images of AT8 immunohistochemistry in tissues sections from the indicated brain regions, showing the principal tau immunostaining patterns identified: dense fibrillar tau filling the neuron cytoplasm (a), vesicular pretangle (b), globose tangle (c), flame shaped-like neurofibrillary tangle (d), thin fibrillary threads in WM (e), pretangle with a diffuse granular cytoplasmic staining (f), vesicular pretangles (g), fibrillary tangle (h), rare small thread-like inclusions in WM tract (i). Images are from donor 1. CN caudate nucleus, CP cerebral peduncle, GM gray matter, MFG middle frontal gyrus, SUB subiculum, WM white matter. Scale bar, 20 µm (shown in a and applies to b–i)
Fig. 3 Tau pathology associated with the V337M mutation. Representative images of AT8 immunohistochemistry in tissues sections from the indicated brain regions, showing the principal tau immunostaining patterns identified: dense fibrillar tau filling the neuron cytoplasm (a), vesicular pretangle (b), globose tangle (c), flame shaped-like neurofibrillary tangle (d), thin fibrillary threads in WM (e), pretangle with a diffuse granular cytoplasmic staining (f), vesicular pretangles (g), fibrillary tangle (h), rare small thread-like inclusions in WM tract (i). Images are from donor 1. CN caudate nucleus, CP cerebral peduncle, GM gray matter, MFG middle frontal gyrus, SUB subiculum, WM white matter. Scale bar, 20 µm (shown in a and applies to b–i)CC BY-NC-ND · PubMed Central
Fig. 4 Tau pathology associated with the P301L mutation. Representative images of AT8 immunohistochemistry in tissues sections from the indicated brain regions, showing the principal tau immunostaining patterns identified: globular astrocytic inclusions (a), granular fuzzy-like astrocytes (b), vesicular pretangles with densely packed cytoplasmic vesicles (c), dense perinuclear rim of bead-like tau fibrillar structures (d), curved threads (blue arrow) and small oval profiles (red arrow) in WM (e), neuron with irregular clumps of cytoplasmic tau (f), thick neurites (red arrow) and perinuclear aggregates (blue arrow) (g), neuron with pretangle morphology and a large clump tau aggregate (h), numerous threads (i). Images are from donor 8. CN caudate nucleus, CP cerebral peduncle, GM gray matter, MFG middle frontal gyrus, SN substantia nigra, WM white matter. Scale bar, 20 µm (shown in a and applies to b–i)
Fig. 4 Tau pathology associated with the P301L mutation. Representative images of AT8 immunohistochemistry in tissues sections from the indicated brain regions, showing the principal tau immunostaining patterns identified: globular astrocytic inclusions (a), granular fuzzy-like astrocytes (b), vesicular pretangles with densely packed cytoplasmic vesicles (c), dense perinuclear rim of bead-like tau fibrillar structures (d), curved threads (blue arrow) and small oval profiles (red arrow) in WM (e), neuron with irregular clumps of cytoplasmic tau (f), thick neurites (red arrow) and perinuclear aggregates (blue arrow) (g), neuron with pretangle morphology and a large clump tau aggregate (h), numerous threads (i). Images are from donor 8. CN caudate nucleus, CP cerebral peduncle, GM gray matter, MFG middle frontal gyrus, SN substantia nigra, WM white matter. Scale bar, 20 µm (shown in a and applies to b–i)CC BY-NC-ND · PubMed Central
Fig. 5 Tau pathology associated with the L284L mutation. Representative images of AT8 immunohistochemistry in tissues sections from the indicated brain regions, showing the principal tau immunostaining patterns identified: large coiled bodies in GM (a), large thick fibrillary coiled bodies in WM (b), circular tau fibrils filling neuron cytoplasm (c), granular fuzzy-like/tufted-like astrocytes (d), coiled bodies in the putamen (e), small ring-like structures (red arrows), and large fibrillar coiled bodies (blue arrows) (f), large grains (g), abundant threads and coiled bodies in WM tract (h), frequent pretangles (i). Images are from donor 17. GM gray matter, IC internal capsule, MFG middle frontal gyrus, PUT putamen, WM white matter, TEC transentorhinal cortex. Scale bar, 20 µm (shown in a and applies to b–i)
Fig. 5 Tau pathology associated with the L284L mutation. Representative images of AT8 immunohistochemistry in tissues sections from the indicated brain regions, showing the principal tau immunostaining patterns identified: large coiled bodies in GM (a), large thick fibrillary coiled bodies in WM (b), circular tau fibrils filling neuron cytoplasm (c), granular fuzzy-like/tufted-like astrocytes (d), coiled bodies in the putamen (e), small ring-like structures (red arrows), and large fibrillar coiled bodies (blue arrows) (f), large grains (g), abundant threads and coiled bodies in WM tract (h), frequent pretangles (i). Images are from donor 17. GM gray matter, IC internal capsule, MFG middle frontal gyrus, PUT putamen, WM white matter, TEC transentorhinal cortex. Scale bar, 20 µm (shown in a and applies to b–i)CC BY-NC-ND · PubMed Central
Fig. 6 MAPT mutation-specific neuropathologic features. NFT neurofibrillary tangle, GAIs globular astrocytic inclusions, CBs coiled bodies, GM gray matter, EC entorhinal cortex, HIPPO hippocampus, TEC transentorhinal cortex
Fig. 6 MAPT mutation-specific neuropathologic features. NFT neurofibrillary tangle, GAIs globular astrocytic inclusions, CBs coiled bodies, GM gray matter, EC entorhinal cortex, HIPPO hippocampus, TEC transentorhinal cortexCC BY-NC-ND · PubMed Central
Fig. 7 Differential gene expression in subjects harboring V337M, P301L, and L284L MAPT mutations in comparison to healthy controls. Heatmaps of differential gene expression in V337M vs controls (a), P301L vs controls (b) and L284L vs controls (c). Blue indicates downregulation and orange indicates upregulation of genes. Volcano plot of differentially expressed genes in V337M vs controls (d), P301L vs controls (e) and L284L vs controls (f). Colored genes are pval < 0.05; blue indicates downregulated genes and red indicated upregulated genes. The top 10 highest fold change genes are labeled
Fig. 7 Differential gene expression in subjects harboring V337M, P301L, and L284L MAPT mutations in comparison to healthy controls. Heatmaps of differential gene expression in V337M vs controls (a), P301L vs controls (b) and L284L vs controls (c). Blue indicates downregulation and orange indicates upregulation of genes. Volcano plot of differentially expressed genes in V337M vs controls (d), P301L vs controls (e) and L284L vs controls (f). Colored genes are pval < 0.05; blue indicates downregulated genes and red indicated upregulated genes. The top 10 highest fold change genes are labeledCC BY-NC-ND · PubMed Central
Fig. 8 nCounter cell type abundance analysis. Heatmaps for cytokine probes in V337M vs controls (a), P301L vs controls (b), and L284L vs controls (c). Blue indicates downregulation and orange indicates upregulation of genes. Cell-type abundance represented by Gene Set Analysis (GSA) in V337M vs controls (d), P301L vs controls (e), and L284L vs controls (f). Blue indicates downregulation and orange indicates upregulation of genes
Fig. 8 nCounter cell type abundance analysis. Heatmaps for cytokine probes in V337M vs controls (a), P301L vs controls (b), and L284L vs controls (c). Blue indicates downregulation and orange indicates upregulation of genes. Cell-type abundance represented by Gene Set Analysis (GSA) in V337M vs controls (d), P301L vs controls (e), and L284L vs controls (f). Blue indicates downregulation and orange indicates upregulation of genesCC BY-NC-ND · PubMed Central

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Cited by

Metadata

Authors
Bogdani, M., Jadhav, V. S., Kraemer, B. C., Grabowski, T. J., Jayadev, S., Domoto-Reilly, K., Liachko, N. F., Bird, T. D., Dirk Keene, C., & Latimer, C. S.
ORCID
Latimer, Caitlin S.
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2026-07-03
Volume
152
Issue
1
ISSN
1432-0533
DOI
10.1007/s00401-026-03047-w
PMC
PMC13331856
Cited by
1
References
12
Language
en
Licence
Funders
  • U.S. Department of Veterans Affairs (IK6BX006467, I01BX005762)
  • National Institutes of Health (RF1AG078374, P30 AG066509, U19AG063911, R01AG066729, U19 AG066567, R01AG090551)
  • U.S. Department of Defense (W81XWH-21-S-TBIPH2)

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

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Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.