Abstract
Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.
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Acknowledgements
This work was supported by Fondation pour la Recherche Médicale (Equipe FRM DEQ20170336711). Two of the neuropathological cases described in this paper (ALZ_441_005 and ALZ_596_006) have been collected by the Neuro-CEB brain bank, Paris, France. We thank Luc Buée for helpful advices and Gabor Kovacs for sharing unpublished data. We thank the technical team at Raymond Escourolle neuropathology department. We thank the ICM-Quant core facility, Paris Brain Institute (ICM). Two patients were included in the Shatau7-Imatau study (NTC025768210). MS, JL and MB acknowledge the chemical/radiopharmaceutical and nursing staff of the Service Hospitalier Frederic Joliot for the synthesis of [11C]-PIB and [18F]-AV-1451 and patient management. MS, JL and MB are also indebted to AVID Radiopharmaceuticals, Inc., for their support in supplying the AV-1451 precursor and chemistry production advice. This study was cofunded by the French Ministry of Health grant (PHRC-2013-0919), CEA, Fondation pour la recherche sur Alzheimer, Institut de recherche internationale Servier, France-Alzheimer.
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Supplementary Fig. 1. Morphological variability at macroscopic examination between the four postmortem studied cases: ALZ_441_005 (a and b), ALZ_595_006 (c), EXT_1198_001 (d), EXT_2001_001 (e). a. Marked atrophy of the frontal, parietal and temporal association cortices. b. Coronal sections at two levels, the head of the caudate and the mamillary bodies, showed marked dilatation of the lateral ventricle, severe atrophy of the striatum (white arrow) and of the temporal lobe (black arrow). The hippocampus and amygdala are barely identifiable. c. Moderate atrophy of the medial temporal lobe (red arrow) associated to a moderate dilatation of the temporal horn of the lateral ventricle. d and e. Absence of brain atrophy. Moderate dilatation of the 3rd ventricle in EXT_2000_001 (e). (a and b) left hemisphere; (c) right hemisphere) (TIFF 20381 KB)
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Supplementary Fig. 2. Diversity of tau pathology in different regions of the brain. In the pallidum, tau pathology was abundant in all cases except in ALZ_596_006. In the substantia nigra tau aggregates where numerous in all cases seen where tissue was available. Globular tau aggregates in neuronal cell body and neuropil threads were the predominating deposits. In the pons, the basis pontis showed a great number of tau positive aggregates which were globular in ALZ_441_005. Tau deposits were scant in EXT_2000_001 and were absent in ALZ_596_006 and EXT_1998_001. The dentate nucleus showed abundant coarse granular neuronal intracytoplasmic aggregates in ALZ_441_005, deposits were moderate in EXT_2000_001 and scant in the other two cases. The white matter showed little pathology in ALZ_596_006 and EXT_2000_001 with few neuropil threads. In ALZ_441_005 a moderate number of oligodendrocytic aggregates were seen and were predominantly globular. In EXT_1998_001, the few oligodendroglial pathology seen adopted a more typical coiled body shape. Immunohistochemical staining with AT8. Scale bar in rows 1-4: 50µm, Scale bar in last row: 25µm (TIFF 9220 KB)
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Supplementary Fig. 3. a. Immunohistochemical and histochemical characteristics of tau aggregates. Tau aggregates seen in neurons and astrocytes in the four histological studied cases (ALZ_441_005, ALZ_596_006, EXT_1998_001, EXT_2000_001) were positive for phosphorylation dependent AT100 antibody, p62 and Gallyas silver staining. Occasional neurons and rarely astrocytes in the frontal cortex of case ALZ_596_006 showed argyrophilic properties with the Bielschowsky silver staining. Frontal cortex (ALZ_441_005 and ALZ_596_006) and striatum (EXT_1998_001 and EXT_2000_001). Immunohistochemistry: AT100 and p62. Silver staining: Gallyas and Bielschowsky. Scale bar 50µm except for Bielschowsy staining of case ALZ_596_006 which is 25µm. b. White matter pathology is scant to moderate in ALZ_441_005. Tau aggregates are seen in some of the oligodendrocytes. There is a predominance of small round aggregates (black arrow) but some coiled bodies are also seen (white arrow head). Tau aggregates express the 3R-tau and 4R-tau isoforms, are AT100 and p62 positive and are argyrophilic with both Gallyas and Bielschowsky silver stains. Immunohistochemistry: AT8, 3R-tau, 4R-tau, AT100 and p62. Silver staining: Gallyas and Bielschowsky. Scale bar for top left image 100µm, for top right image 50µm and for inferior row 25µm. c. Only rare neurons in the dentate gyrus and CA2 region of the hippocampus are positive for Bielschowsky in ALZ_441_005. Bielschowsky silver stain. Scale bar: 25µm. d. Round neuronal intracytoplasmic tau aggregates were observed in the dentate gyrus in ALZ_596_006. The aggregates were immunoreactive for both 3R-tau and 4R-tau antibodies and were positive for Gallyas and Bielschowsky silver staining. Immunohistochemistry: 3R-tau and 4R-tau. Silver stains: Gallyas and Bielschowsky. Scale bar: 25µm. e. Perivascular thorny astrocytes reminiscent of aging-related tau astrogliopathy (ARTAG) were seen in the periamygdaloid region. Additionally, there were occasional astrocytes containing tau aggregates in the subcortical white matter (parietal lobe). Immunohistochemistry: AT8. Scale bar: 50µm. f. In case ALZ_596_006, 3R tau and 4R tau neurofibrillary tangles and neuropil threads in the hippocampus-CA1. Immunohistochemistry: 3R-tau, 4R-tau. Silver staining: Gallyas and Bielschowsky. Scale bar: 50 µm (TIFF 7107 KB)
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Supplementary Fig. 4. Western blot using WO2 antibody from the frontal cortex of three MAPT duplication carriers, a subject with Alzheimer disease due to an APP duplication, and one normal control (TIFF 10263 KB)
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Supplementary Fig. 5. Analysis of the 4R/3R ratio of MAPT mRNA. Extracted from frontal cortex or striatum. The control group (ctrls) consists in the mean of five normal individuals. Error bars represent SEM. ALZ 441: ALZ_441_005; ALZ 596: ALZ_596_006, EXT 1998: EXT_1998_001 (TIFF 7134 KB)
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Supplementary Fig. 6. Quantitative analysis of tau seeding activity in a cell biosensor. Proportion of HEK cells containing endogenous tau intracellular aggregates for each tested sample, obtained after 2 x 4 repeated observations in three independent experiments. Patients were compared into a linear mixed effect model for repeated data using Tukey correction for multiple comparisons (Mean of observed proportions ± SEM: CTRL: 0.22% ± 0.11%, PiD cortex: 2.90% ± 0.51%; ALZ_441_005 striatum: 12.22 ± 0.81; ALZ_596_006: 4.48 ± 0.61% ; EXT_1998_001 striatum: 5.95% ± 0.83%; PSP : 14.93% ± 0.90% ). Proportion of cells with aggregates is significantly higher in all patients compared to controls (PiD vs CTRL: p=0.01; other comparison to controls: all p<0.001). Tau seeding activities detected in patients were all pairwise significantly different (ALZ_441_005 vs PSP: p=0.03, EXT_1998_001 vs PiD: p = 0.01, all other p<0.001) except for PiD vs ALZ_596_006 (p=0.6) and EXT_1998_001 vs ALZ_596_006 (p=0.6) (TIFF 6775 KB)
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Supplementary Fig 7. Absence of associated ⍺-synucleinopathy or TDP-43-pathy. Immunohistochemistry for ⍺-synuclein and TDP-43 was negative in all histological studied cases. Aβ was negative in three cases (ALZ_441_005, EXT_1998_001, EXT_2000_001). A few diffuse plaques were seen in the neocortex of ALZ_596_006. First column: frontal cortex. Second column: substantia nigra (SN). Third column: dentate gyrus. Scale bar: 50 µm (TIFF 12293 KB)
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Supplementary Table 1. Staining properties of tau immunoreactive aggregates in different cell types in MAPT duplication carriers. 3R-tau, 4R-tau, AT100 and p62 antibodies. Gallyas and Bielschowsky silver staining. R: tau aggregates are sparsely positive. ND: not determined. (DOCX 18 kb)
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Wallon, D., Boluda, S., Rovelet-Lecrux, A. et al. Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers. Acta Neuropathol 142, 259–278 (2021). https://doi.org/10.1007/s00401-021-02320-4
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DOI: https://doi.org/10.1007/s00401-021-02320-4