Acetylated Tau Neuropathology in Sporadic and Hereditary Tauopathies
2013; Elsevier BV; Volume: 183; Issue: 2 Linguagem: Inglês
10.1016/j.ajpath.2013.04.025
ISSN1525-2191
AutoresDavid J. Irwin, Todd J. Cohen, Murray Grossman, Steven E. Arnold, Elisabeth McCarty-Wood, Vivianna M. Van Deerlin, Virginia M.‐Y. Lee, John Q. Trojanowski,
Tópico(s)Parkinson's Disease Mechanisms and Treatments
ResumoWe have recently shown acetylation of tau at lysine residue 280 (AC-K280) to be a disease-specific modification in Alzheimer disease (AD), corticobasal degeneration, and progressive supranuclear palsy, likely representing a major regulatory tau modification. Herein, we extend our observations using IHC with a polyclonal antibody specific for AC-K280. Thirty brain regions were examined in argyrophilic grain disease (AGD; n = 5), tangle-predominant senile dementia (TPSD; n = 5), Pick disease (n = 4), familial AD (FAD; n = 2; PSEN1 p.G206A and p.S170P), and frontotemporal dementia with parkinsonism linked to chromosome-17 (FTDP-17; n = 2; MAPT p.P301L and IVS10 + 16). All AGD, TPSD, FAD, and FTDP-17 cases had significant AC-K280 reactivity that was similar in severity and distribution to phosphorylated tau. AC-K280 robustly labeled grain pathological characteristics in AGD and was predominantly associated with thioflavin-S–positive neurofibrillary tangles and less reactive in neuropil threads and extracellular tangles in TPSD and FAD. Thioflavin-S–negative neuronal and glial inclusions of patients with FTDP-17 were robustly AC-K280 reactive. A low degree of AC-K280 was found in a subset of 4-repeat tau-containing lesions in Pick disease. AC-K280 is a prominent feature of both neuronal and glial tau aggregations in tauopathies of various etiologies. The close association of AC-K280 with amyloid and pre-amyloid conformations of tau suggests a potential role in tangle maturation and, thus, could serve as a useful biomarker or therapeutic target in a variety of tauopathies. We have recently shown acetylation of tau at lysine residue 280 (AC-K280) to be a disease-specific modification in Alzheimer disease (AD), corticobasal degeneration, and progressive supranuclear palsy, likely representing a major regulatory tau modification. Herein, we extend our observations using IHC with a polyclonal antibody specific for AC-K280. Thirty brain regions were examined in argyrophilic grain disease (AGD; n = 5), tangle-predominant senile dementia (TPSD; n = 5), Pick disease (n = 4), familial AD (FAD; n = 2; PSEN1 p.G206A and p.S170P), and frontotemporal dementia with parkinsonism linked to chromosome-17 (FTDP-17; n = 2; MAPT p.P301L and IVS10 + 16). All AGD, TPSD, FAD, and FTDP-17 cases had significant AC-K280 reactivity that was similar in severity and distribution to phosphorylated tau. AC-K280 robustly labeled grain pathological characteristics in AGD and was predominantly associated with thioflavin-S–positive neurofibrillary tangles and less reactive in neuropil threads and extracellular tangles in TPSD and FAD. Thioflavin-S–negative neuronal and glial inclusions of patients with FTDP-17 were robustly AC-K280 reactive. A low degree of AC-K280 was found in a subset of 4-repeat tau-containing lesions in Pick disease. AC-K280 is a prominent feature of both neuronal and glial tau aggregations in tauopathies of various etiologies. The close association of AC-K280 with amyloid and pre-amyloid conformations of tau suggests a potential role in tangle maturation and, thus, could serve as a useful biomarker or therapeutic target in a variety of tauopathies. Tauopathies are a heterogeneous group of neurodegenerative diseases characterized by abnormal conformations of tau proteins incorporated into inclusions and resulting in neuronal loss and gliosis. Pathogenic mutations in the MAPT tau gene causing frontotemporal dementia with parkinsonism linked to chromosome-17 (FTDP-17),1Hutton M. Lendon C.L. Rizzu P. Baker M. Froelich S. Houlden H. et al.Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17.Nature. 1998; 393: 702-705Crossref PubMed Scopus (2927) Google Scholar with characteristic tau lesions at autopsy, provide compelling evidence of a central role of tau aggregation in disease pathogenesis. Tau is subject to multiple post-translational modifications that, in disease states, may become dysregulated and contribute to pathological aggregation.2Lee V.M. Goedert M. Trojanowski J.Q. Neurodegenerative tauopathies.Annu Rev Neurosci. 2001; 24: 1121-1159Crossref PubMed Scopus (2162) Google Scholar Previously, our group3Cohen T.J. Guo J.L. Hurtado D.E. Kwong L.K. Mills I.P. Trojanowski J.Q. Lee V.M. The acetylation of tau inhibits its function and promotes pathological tau aggregation.Nat Commun. 2011; 2: 252Crossref PubMed Scopus (494) Google Scholar and others4Min S.W. Cho S.H. Zhou Y. Schroeder S. Haroutunian V. Seeley W.W. Huang E.J. Shen Y. Masliah E. Mukherjee C. Meyers D. Cole P.A. Ott M. Gan L. Acetylation of tau inhibits its degradation and contributes to tauopathy.Neuron. 2010; 67: 953-966Abstract Full Text Full Text PDF PubMed Scopus (700) Google Scholar have found that tau is modified by acetylation on lysine residues within the microtubule (MT)–binding domain (MTBD). Two main categories of tau isoforms exist, based on alternative splicing of exon 10 for inclusion or exclusion of the second MTBD for a total of 3 (3R) or 4 (4R) MTBD repeats. We found acetylation of lysine 280 (AC-K280) in the second MTBD in 4R tau to be disease specific, resulting in both decreased microtubule binding and increased fibrillization in vitro.3Cohen T.J. Guo J.L. Hurtado D.E. Kwong L.K. Mills I.P. Trojanowski J.Q. Lee V.M. The acetylation of tau inhibits its function and promotes pathological tau aggregation.Nat Commun. 2011; 2: 252Crossref PubMed Scopus (494) Google Scholar Furthermore, AC-K280 is a prominent marker of pathological characteristics in Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP).5Irwin D.J. Cohen T.J. Grossman M. Arnold S.E. Xie S.X. Lee V.M. Trojanowski J.Q. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies.Brain. 2012; 135: 807-818Crossref PubMed Scopus (199) Google Scholar Herein, we further examine the AC-K280 modification in other sporadic and hereditary tauopathies characterized by insoluble 4R tau-predominant filaments, including argyrophilic grain disease (AGD), tangle-predominant senile dementia (TPSD), FTDP-17, and familial AD (FAD) cases caused by presenillin-1 (PSEN1) mutations. We also examined cases of the predominantly 3R tauopathy, Pick disease (PiD), because heterogeneity exists in the tau isoform profile in insoluble deposits of tau in the brains of patients with PiD.6Zhukareva V. Mann D. Pickering-Brown S. Uryu K. Shuck T. Shah K. Grossman M. Miller B.L. Hulette C.M. Feinstein S.C. Trojanowski J.Q. Lee V.M. Sporadic Pick's disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white matter.Ann Neurol. 2002; 51: 730-739Crossref PubMed Scopus (144) Google Scholar, 7Arai T. Ikeda K. Akiyama H. Shikamoto Y. Tsuchiya K. Yagishita S. Beach T. Rogers J. Schwab C. McGeer P.L. Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick's disease, corticobasal degeneration and progressive supranuclear palsy.Acta Neuropathol. 2001; 101: 167-173Crossref PubMed Scopus (169) Google Scholar, 8Yoshida M. Cellular tau pathology and immunohistochemical study of tau isoforms in sporadic tauopathies.Neuropathology. 2006; 26: 457-470Crossref PubMed Scopus (91) Google Scholar Patients were seen at the University of Pennsylvania Perelman School of Medicine (Philadelphia) Alzheimer's Disease Center or Frontotemporal Degeneration Center, and autopsies were performed at the Center for Neurodegenerative Disease Research. Autopsies were performed with informed consent, and all procedures were done in accordance with the local Institutional Review Board guidelines. Patient demographics were obtained from our integrated neurodegenerative disease database9Xie S.X. Baek Y. Grossman M. Arnold S.E. Karlawish J. Siderowf A. Hurtig H. Elman L. McCluskey L. Van Deerlin V. Lee V.M. Trojanowski J.Q. Building an integrated neurodegenerative disease database at an academic health center.Alzheimers Dement. 2011; 7: e84-e93Crossref PubMed Scopus (51) Google Scholar (Supplemental Table S1). Neuropathological assessment and diagnosis were performed as reported previously10Forman M.S. Farmer J. Johnson J.K. Clark C.M. Arnold S.E. Coslett H.B. Chatterjee A. Hurtig H.I. Karlawish J.H. Rosen H.J. Van Deerlin V. Lee V.M. Miller B.L. Trojanowski J.Q. Grossman M. Frontotemporal dementia: clinicopathological correlations.Ann Neurol. 2006; 59: 952-962Crossref PubMed Scopus (395) Google Scholar using established criteria.11Mackenzie I.R. Neumann M. Bigio E.H. Cairns N.J. Alafuzoff I. Kril J. Kovacs G.G. Ghetti B. Halliday G. Holm I.E. Ince P.G. Kamphorst W. Revesz T. Rozemuller A.J. Kumar-Singh S. Akiyama H. Baborie A. Spina S. Dickson D.W. Trojanowski J.Q. Mann D.M. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update.Acta Neuropathol. 2010; 119: 1-4Crossref PubMed Scopus (738) Google Scholar, 12Montine T.J. Phelps C.H. Beach T.G. Bigio E.H. Cairns N.J. Dickson D.W. Duyckaerts C. Frosch M.P. Masliah E. Mirra S.S. Nelson P.T. Schneider J.A. Thal D.R. Trojanowski J.Q. Vinters H.V. Hyman B.T. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach.Acta Neuropathol. 2012; 123: 1-11Crossref PubMed Scopus (1573) Google Scholar Tau and amyloid β pathological characteristics were staged according to Braak and Braak13Braak H. Braak E. Neuropathological stageing of Alzheimer-related changes.Acta Neuropathol. 1991; 82: 239-259Crossref PubMed Scopus (11766) Google Scholar and the Consortium to Establish a Registry for Alzheimer's Disease14Mirra S.S. Heyman A. McKeel D. Sumi S.M. Crain B.J. Brownlee L.M. Vogel F.S. Hughes J.P. van Belle G. Berg L. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD), part II: standardization of the neuropathologic assessment of Alzheimer's disease.Neurology. 1991; 41: 479-486Crossref PubMed Google Scholar criteria, respectively. AGD cases were staged according to Ferrer et al.15Ferrer I. Santpere G. van Leeuwen F.W. Argyrophilic grain disease.Brain. 2008; 131: 1416-1432Crossref PubMed Scopus (149) Google Scholar Thirty areas were sampled and analyzed for five cases each of AGD and TPSD, four cases of PiD, and several hereditary FAD and FTDP-17 cases [n = 1: PSEN1 p.G206A,16Arnold S.E. Vega I.E. Karlawish J.H. Wolk D.A. Nunez J. Negron M. Xie S.X. Wang L.S. Dubroff J.G. McCarty-Wood E. Trojanowski J.Q. Van Deerlin V. Frequency and clinicopathological characteristics of presenilin 1 Gly206Ala mutation in Puerto Rican Hispanics with dementia.J Alzheimers Dis. 2013; 33: 1089-1095Crossref PubMed Scopus (18) Google Scholar PSEN1 p.S170P, MAPT p.P301L,1Hutton M. Lendon C.L. Rizzu P. Baker M. Froelich S. Houlden H. et al.Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17.Nature. 1998; 393: 702-705Crossref PubMed Scopus (2927) Google Scholar and MAPT IVS10 + 16 (c.915 + 16C>T)1Hutton M. Lendon C.L. Rizzu P. Baker M. Froelich S. Houlden H. et al.Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17.Nature. 1998; 393: 702-705Crossref PubMed Scopus (2927) Google Scholar]. We also examined available regions in two nonneurodegenerative control cases (Braak stage 0) (Supplemental Table S1). The PSEN1 p.S170P mutation has not been previously reported, but it is likely pathogenic in view of the extremely young age of disease onset (27 years) in this patient and the family history of AD among the kindred of this patient (Supplemental Figure S1), as well as a similar reported pathogenic mutation at this residue (p.S170F).17Snider B.J. Norton J. Coats M.A. Chakraverty S. Hou C.E. Jervis R. Lendon C.L. Goate A.M. McKeel Jr., D.W. Morris J.C. Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life.Arch Neurol. 2005; 62: 1821-1830Crossref PubMed Scopus (108) Google Scholar Fresh tissue was sampled at autopsy and fixed in 70% ethanol/150 mmol sodium chloride, embedded in paraffin, and cut into sections (6 μm thick). Immunohistochemistry (IHC) was performed, as previously described,5Irwin D.J. Cohen T.J. Grossman M. Arnold S.E. Xie S.X. Lee V.M. Trojanowski J.Q. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies.Brain. 2012; 135: 807-818Crossref PubMed Scopus (199) Google Scholar using a rabbit-generated polyclonal antibody specific for tau modified with an acetyl group at the 280 lysine (K) residue3Cohen T.J. Guo J.L. Hurtado D.E. Kwong L.K. Mills I.P. Trojanowski J.Q. Lee V.M. The acetylation of tau inhibits its function and promotes pathological tau aggregation.Nat Commun. 2011; 2: 252Crossref PubMed Scopus (494) Google Scholar (AC-K280; 1:250 to 1:1000 dilution) and an avidin-biotin complex detection system (VECTASTAIN ABC kit; Vector Laboratories, Burlingame, CA) with 3,3′-diaminobenzidine as the chromogen. AC-K280 specificity for the modified lysine residue has been described in detail.3Cohen T.J. Guo J.L. Hurtado D.E. Kwong L.K. Mills I.P. Trojanowski J.Q. Lee V.M. The acetylation of tau inhibits its function and promotes pathological tau aggregation.Nat Commun. 2011; 2: 252Crossref PubMed Scopus (494) Google Scholar Mouse monoclonal antibodies (mAbs) specific for other tau epitopes were used herein, and they include phosphorylated tau [PHF-118Otvos Jr., L. Feiner L. Lang E. Szendrei G.I. Goedert M. Lee V.M. Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404.J Neurosci Res. 1994; 39: 669-673Crossref PubMed Scopus (409) Google Scholar; 1:500 to 1:1000; courtesy of Dr. Peter Davies (Albert Einstein College of Medicine, Department of Pathology, Bronx, NY)] and 3R (RD319de Silva R. Lashley T. Gibb G. Hanger D. Hope A. Reid A. Bandopadhyay R. Utton M. Strand C. Jowett T. Khan N. Anderton B. Wood N. Holton J. Revesz T. Lees A. Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies.Neuropathol Appl Neurobiol. 2003; 29: 288-302Crossref PubMed Scopus (180) Google Scholar; 1:2500 to 1:5000; Millipore, Billerica, MA) and 4R (RD419de Silva R. Lashley T. Gibb G. Hanger D. Hope A. Reid A. Bandopadhyay R. Utton M. Strand C. Jowett T. Khan N. Anderton B. Wood N. Holton J. Revesz T. Lees A. Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies.Neuropathol Appl Neurobiol. 2003; 29: 288-302Crossref PubMed Scopus (180) Google Scholar; 1:5000 to 1:10,000; Millipore) tau isoforms. Antigen retrieval was performed by using 88% formic acid for AC-K280 and RD3 or boiling with a citric acid unmasking solution (Vector Laboratories) for RD4. Double-label immunofluorescence experiments were performed as described5Irwin D.J. Cohen T.J. Grossman M. Arnold S.E. Xie S.X. Lee V.M. Trojanowski J.Q. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies.Brain. 2012; 135: 807-818Crossref PubMed Scopus (199) Google Scholar using AC-K280 and tau-specific mAbs or thioflavin-S (ThS) amyloid dye staining for fibrillar inclusions and Alexa Fluor 488 and 594 species-specific conjugated secondary antibodies (Invitrogen, Grand Island, NY). To confirm the 4R tau predominance in AGD grains and presence of 4R tau in PiD cases, serial sections and double-label experiments with AC-K280 and RD3/RD4 were performed on hippocampal sections of AGD (n = 4) and three areas of high AC-K280 reactivity in one PiD case (anterior cingulate gyrus, motor cortex, and temporal cortex). ThS and AC-K280 double labeling was also examined in these regions for AGD and PiD and, in addition, in TPSD hippocampus (n = 4), FAD hippocampus or frontal cortex (n = 2), and FTDP-17 hippocampus or temporal neocortex (n = 2). Digital images of immunofluorescence were obtained with an Olympus BX 51 microscope equipped with a bright-field and fluorescence light source with a DP-71 digital camera (Olympus, Center Valley, PA) and DP manager software version 3.1.1.208 (Olympus) and overlaid into a merge channel using Adobe Photoshop version 9.0.2 (Adobe Systems, San Jose, CA). For the hereditary cases in this study, DNA was extracted from peripheral blood samples or brain tissue using the manufacturer's protocol (Flexigene; Qiagen, Valencia, CA) or the Quick-Gene DNA whole blood kit (Autogen, Holliston, MA). DNA sequence analysis of the entire coding region of PSEN1 and targeted regions of MAPT known to harbor pathogenic mutations (exons 1 and 9 to 13) was performed as previously described.16Arnold S.E. Vega I.E. Karlawish J.H. Wolk D.A. Nunez J. Negron M. Xie S.X. Wang L.S. Dubroff J.G. McCarty-Wood E. Trojanowski J.Q. Van Deerlin V. Frequency and clinicopathological characteristics of presenilin 1 Gly206Ala mutation in Puerto Rican Hispanics with dementia.J Alzheimers Dis. 2013; 33: 1089-1095Crossref PubMed Scopus (18) Google Scholar, 20Van Deerlin V.M. Gill L.H. Farmer J.M. Trojanowski J.Q. Lee V.M. Familial frontotemporal dementia: from gene discovery to clinical molecular diagnostics.Clin Chem. 2003; 49: 1717-1725Crossref PubMed Scopus (19) Google Scholar Data were analyzed for identification of mutations with Mutation Surveyor software version 4.0.7 (Soft Genetics, State College, PA). Regional distribution and severity of AC-K280 were compared with PHF-1 across 30 representative central nervous system regions and graded on a semiquantitative scale, as previously described5Irwin D.J. Cohen T.J. Grossman M. Arnold S.E. Xie S.X. Lee V.M. Trojanowski J.Q. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies.Brain. 2012; 135: 807-818Crossref PubMed Scopus (199) Google Scholar (0, none or rare pathological feature; 1, weak; 2, moderate; and 3, strong). Median semiquantitative scores for grouped data were calculated for each region per disease group using SPSS, version 19.0 (SPSS Inc., Chicago, IL). Detailed neuropathological assessment in 30 representative cortical and subcortical regions of the CNS revealed AC-K280 in a similar distribution and severity to the well-described PHF-1 phosphorylated-epitope of tau (Ser396/404)18Otvos Jr., L. Feiner L. Lang E. Szendrei G.I. Goedert M. Lee V.M. Monoclonal antibody PHF-1 recognizes tau protein phosphorylated at serine residues 396 and 404.J Neurosci Res. 1994; 39: 669-673Crossref PubMed Scopus (409) Google Scholar in AGD, TPSD, FAD, and FTDP-17 cases (Figure 1 and Supplemental Tables S2, S3, and S4). AC-K280 immunoreactivity was not found in areas negative for PHF-1, and, similarly, in regions with weak or rare PHF-1 pathological features, there was often no detectable AC-K280. This was also true in control cases, in which AC-K280 was limited to rare (one to three tangles) in the cornu ammonis in one case; these were also detected with PHF-1 in an adjacent section (Figure 2 and Supplemental Table S4). Only rarely in FTDP-17 did AC-K280 immunoreactivity appear slightly more prominent than PHF-1 (Supplemental Table S4). PiD cases were largely negative for AC-K280; however, a subset of regions in each PiD case contained a varying degree of AC-K280 immunoreactivity (Table 1). In most instances when AC-K280 immunoreactivity was present, it was found in rare (one to five per slide) glial inclusions or Pick bodies, although one case had three regions with an abundance of AC-K280 lesions. The fourth case had only rare AC-K280 tau pathological characteristics in the entorhinal cortex of the hippocampus.Figure 2Acetylated and hyperphosphorylated tau pathological characteristics in sporadic and hereditary tauopathies. A–P: Representative images of AC-K280 staining and B-R display PHF-1 staining. Sections from the amygdala in AGD show prominent AC-K280–reactive grains (arrowheads; A and C) and neurofibrillary tangles (NFTs; asterisk; A) and ballooned neurons (asterisk; C) similar to PHF-1 (B and D). AC-K280 reactivity in the cornu ammonis (CA-1) region of the hippocampus in TPSD is seen mostly in intracellular tangles (arrow; E), with less prominent staining of threads and extracellular ghost tangles labeled by PHF-1 (F). CA-1 region of the hippocampus of a PSEN1 case (p.S170P) displays typical AD pathological characteristics, with AC-K280 mainly in tangles (asterisk) and neuritic plaques (arrow; G) and less prominent in diffuse threads than PHF-1 (H). Superior temporal cortex (STC) of FTDP-17 cases (p.P301L and IVS10 + 16) have ACK280-reactive neuronal inclusions (I and M) and less prominent threads than PHF-1 (J and N) in gray matter (GM) and a similar burden of glial tau pathological features in white matter (WM; arrow; K and L). Nonneurodegnerative disease control superior temporal cortex showing an absence of AC-K280 (Q) and PHF-1 reactivity (R). Scale bar = 100 μm (R).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Summary of AC-K280 Reactivity in PiD CasesRegionCase no.1234Motor+++Rare0NAStriatum00++0Lentiform00Rare0Thalamus00RareNAHypothalamusRare+NANAMidbrain0000Substantia nigra00Rare0Pons0000Locus coeruleus00Rare0Cerebellar cortex0000Dentate nucleus or cerebellum0000Medulla0000Cervical spinal cord0000Midfrontal cortexRareRare+0Orbital frontal cortex0Rare00Anterior cingulate cortex+++0+0Sensory cortexRare0NA0Temporal cortex+++000Angular cortexRare000Visual cortex00NA0Entorhinal cortex or hippocampusRareRare0RareCornu ammonis or hippocampus0000Dentate gyrus or hippocampus0000AmygdalaRare+00+, weak; ++, moderate ; +++, strong.NA, tissue not available. Open table in a new tab +, weak; ++, moderate ; +++, strong. NA, tissue not available. AC-K280 was robust in tau-positive comma-shaped grains in all five AGD cases studied herein (Figure 2), which were largely restricted to limbic areas (one stage II and four stage III). PHF-1–positive intracellular pretangles and neurofibrillary tangles (NFTs), in addition to lightly tau-reactive swollen achromatic ballooned neurons and coiled bodies in adjacent white matter, were also labeled by AC-K280 (Figure 2). AC-K280 was found in predominantly ThS-positive NFTs and variably ThS-positive grains (Figure 3). Comparison with isoform-specific tau mAbs confirmed the predominance of 4R tau in grains, because the 4R-specific tau mAb (RD4) displayed a similar predominance of intracellular NFTs and grains to AC-K280, whereas a 3R-specific mAb (RD3) mainly labeled AD-associated extracellular ghost tangles and diffuse neuropil threads (NTs) that were not well labeled by the AC-K280 antibody (Supplemental Figure S2). AC-K280 colocalized well with RD4 in grains that were largely RD3 negative, and colocalized with both isoform-specific mAbs in intracellular NFTs (Supplemental Figure S2). TPSD cases had a predominance of PHF-1–reactive NFTs similar to AD in the absence of significant amyloid β deposits (Supplemental Table S1). AC-K280 was a prominent feature of intracellular NFTs and less conspicuous in extracellular ghost tangles and diffuse scattered NTs (Figure 2). Most AC-280–reactive NFTs in CA-1 were ThS positive (Figure 3). A subset of cases had more widespread tau pathological characteristics outside of the medial temporal lobe structures (Braak V to VI, n = 2). These cases had abundant tau-positive tangles and threads in the medial and lateral temporal lobe cortical regions, with occasional tau-positive glial inclusions largely restricted to gray matter, with some compact lesions reminiscent of tufted astrocytes in PSP and other, more diffuse, lesions resembling astrocytic plaques of CBD. However, the lack of significant white matter tau pathological characteristics and infrequent tau inclusions in the brainstem precluded these diagnoses and, thus, these findings were most consistent with a diagnosis of TPSD. AC-K280 immunoreactivity appeared similar in these cases, with prominent deposition in neuronal tangles and glial lesions, with minimal positivity in NTs or extracellular ghost tangles. Both the PSEN1 p.G206A and p.S170P FAD cases displayed typical AD tau pathological features, with widespread NTs, NFTs, and neuritic plaques throughout cortical and, to a lesser degree, subcortical structures (Supplemental Table S4). Similar to sporadic AD,5Irwin D.J. Cohen T.J. Grossman M. Arnold S.E. Xie S.X. Lee V.M. Trojanowski J.Q. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies.Brain. 2012; 135: 807-818Crossref PubMed Scopus (199) Google Scholar AC-K280 stained all forms of neurofibrillary pathological features but was most prominent in ThS-positive intracellular NFTs and large dystrophic neurites associated with neuritic plaques and was less reactive to other NTs and extracellular NFTs (Figures 2 and 3). FTDP-17 cases had microscopic findings consistent with previous reports of abundant and widespread tau pathological characteristics, albeit in different distributions in cases that resembled PSP or CBD versus other phenotypic manifestations of MAPT gene mutations.21Lantos P.L. Cairns N.J. Khan M.N. King A. Revesz T. Janssen J.C. Morris H. Rossor M.N. Neuropathologic variation in frontotemporal dementia due to the intronic tau 10(+16) mutation.Neurology. 2002; 58: 1169-1175Crossref PubMed Scopus (40) Google Scholar, 22Nasreddine Z.S. Loginov M. Clark L.N. Lamarche J. Miller B.L. Lamontagne A. Zhukareva V. Lee V.M. Wilhelmsen K.C. Geschwind D.H. From genotype to phenotype: a clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation.Ann Neurol. 1999; 45: 704-715Crossref PubMed Scopus (128) Google Scholar The p.P301L case showed widespread strong immunoreactivity in tau deposits throughout cortical and subcortical gray matter and, to a lesser extent, white matter (Supplemental Table S4). Pleomorphic neuronal tangles were prominent in superficial and deep cortical layers and were robustly reactive with AC-K280, whereas associated diffuse threads seen with PHF-1 were less evident in AC-K280–stained sections (Figure 2). Pick-like bodies were rarely observed with either epitope. Glial pathological features were moderate and mainly found in coiled bodies and astrocytic lesions in white matter, both of which were reactive to AC-K280 (Figure 2). In contrast, the IVS10 + 16 case had less prominent neuronal tau inclusions and threads in gray matter and, instead, strong immunostaining in white matter glial pathological features throughout the neocortex and limbic cortices (Figure 2). Glial pathological features were robustly positive for AC-K280 and, in rare instances, slightly more prominent than PHF-1 (Supplemental Table S4). AC-K280–reactive pathological characteristics in FTDP-17 cases were largely negative for ThS (Figure 3). In summary, AC-K280 was a prominent feature of the varied glial and neuronal inclusions and less common in diffuse threads seen in these FTDP-17 cases. Although PHF-1 and RD3 staining revealed numerous tau-positive inclusions and diffusely distributed NTs, only a minimal subset of tau lesions in the PiD cases was AC-K280 immunoreactive, and these included Pick bodies and compact astrocytic inclusions (Supplemental Figure S3). Areas with strong AC-K280 immunostaining in neuronal Pick body and glial inclusions were confirmed to contain 4R tau through comparison of serial sections and double labeling with RD4. The morphological characteristics of the AC-K280–positive inclusions were similar to the RD4-stained inclusions and both colocalized in neuronal and glial lesions, whereas double labeling with RD3 demonstrated that some RD3-labeled inclusions colocalized in the AC-K280–positive tau pathological characteristics, but most often RD3 positivity did not colocalize in AC-K280 (Supplemental Figure S3). PiD inclusions, including those reactive to AC-K280, were weakly reactive for ThS (Supplemental Figure S3). We extend our previous studies of acetylated tau pathological characteristics by documenting the presence of AC-K280 immunoreactivity in the hallmark tau lesions of AGD, TPSD, FAD, and FTDP-17 in a similar pattern and severity to a well-annotated phosphorylated-epitope (Ser396/404). Furthermore, we have also demonstrated the disease-specific nature of the AC-K280 modification because little or no AC-K280 reactivity was found in the control cases examined herein (Supplemental Table S4) or in previous studies.3Cohen T.J. Guo J.L. Hurtado D.E. Kwong L.K. Mills I.P. Trojanowski J.Q. Lee V.M. The acetylation of tau inhibits its function and promotes pathological tau aggregation.Nat Commun. 2011; 2: 252Crossref PubMed Scopus (494) Google Scholar, 5Irwin D.J. Cohen T.J. Grossman M. Arnold S.E. Xie S.X. Lee V.M. Trojanowski J.Q. Acetylated tau, a novel pathological signature in Alzheimer's disease and other tauopathies.Brain. 2012; 135: 807-818Crossref PubMed Scopus (199) Google Scholar AC-K280 also detected tau pathological characteristics in PiD, although to a much lesser extent and more variable degree, reflecting the low burden of 4R tau inclusions in most PiD cases. PiD is considered to be a 3R tauopathy, although some cases have been found to have a variable, but significant, burden of 4R tau-positive lesions or insoluble 4R species of pathological tau.6Zhukareva V. Mann D. Pickering-Brown S. Uryu K. Shuck T. Shah K. Grossman M. Miller B.L. Hulette C.M. Feinstein S.C. Trojanowski J.Q. Lee V.M. Sporadic Pick's disease: a tauopathy characterized by a spectrum of pathological tau isoforms in gray and white
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