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Molecular Neurodegeneration
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Open Access 01-12-2024 | Alzheimer's Disease | Research article

Seeding activity of skin misfolded tau as a biomarker for tauopathies

Authors: Zerui Wang, Ling Wu, Maria Gerasimenko, Tricia Gilliland, Zahid Syed Ali Shah, Evalynn Lomax, Yirong Yang, Steven A. Gunzler, Vincenzo Donadio, Rocco Liguori, Bin Xu, Wen-Quan Zou

Published in: Molecular Neurodegeneration | Issue 1/2024

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Abstract

Background

Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically hyperphosphorylated tau protein in the brain, leading to prion-like aggregation and propagation. They include Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick’s disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking.

Methods

We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls.

Results

We found that the skin tau-SAA demonstrated a significantly higher sensitivity (75–80%) and specificity (95–100%) for detecting tauopathy, depending on the tau substrates used. Moreover, the increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used.

Conclusions

Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies.
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Literature
1.
2.
3.
Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron. 1989;3:519–26.PubMedCrossRef
4.
5.
Zhang K, Mizuma H, Zhang X, Takahashi K, Jin C, Song F, et al. PET imaging of neural activity, β-amyloid, and tau in normal brain aging. Eur J Nucl Med Mol Imaging. 2021;48:3859–71.PubMedCrossRef
6.
7.
Orrù CD, Isiofia O, Hughson AG, Caughey B. Real-Time Quaking-Induced Conversion (QuIC) Assays for the Detection and Diagnosis of Human Prion Diseases. In: Zou W-Q, Gambetti P, editors. Prions Dis. Cham: Springer International Publishing; 2023. pp. 621–35. https://​doi.​org/​10.​1007/​978-3-031-20565-1_​30. [cited 2023 Aug 21].
8.
9.
Atarashi R, Satoh K, Sano K, Fuse T, Yamaguchi N, Ishibashi D, et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat Med. 2011;17:175–8.PubMedCrossRef
10.
Fairfoul G, McGuire LI, Pal S, Ironside JW, Neumann J, Christie S, et al. Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies. Ann Clin Transl Neurol. 2016;3:812–8.PubMedPubMedCentralCrossRef
11.
Groveman BR, Orrù CD, Hughson AG, Raymond LD, Zanusso G, Ghetti B, et al. Rapid and ultra-sensitive quantitation of disease-associated α-synuclein seeds in brain and cerebrospinal fluid by αSyn RT-QuIC. Acta Neuropathol Commun. 2018;6:7.PubMedPubMedCentralCrossRef
12.
Orrù CD, Groveman BR, Hughson AG, Manca M, Raymond LD, Raymond GJ, et al. RT-QuIC assays for Prion Disease Detection and Diagnostics. Methods Mol Biol Clifton NJ. 2017;1658:185–203.CrossRef
13.
Orrù CD, Groveman BR, Raymond LD, Hughson AG, Nonno R, Zou W, et al. Bank Vole prion protein as an apparently universal substrate for RT-QuIC-Based detection and discrimination of prion strains. PLoS Pathog. 2015;11:e1004983M.CrossRef
14.
Shahnawaz T, Tokuda M, Waragai N, Mendez R, Ishii C, Trenkwalder B, Mollenhauer C, Soto. Development of a biochemical diagnosis of Parkinson Disease by detection of α-Synuclein misfolded aggregates in Cerebrospinal Fluid. JAMA Neurol. 2017;74:163–72.PubMedCrossRef
15.
Wang Z, Becker K, Donadio V, Siedlak S, Yuan J, Rezaee M, et al. Skin α-Synuclein aggregation seeding activity as a Novel Biomarker for Parkinson Disease. JAMA Neurol. 2020;78:1–11.PubMedPubMedCentral
16.
Kraus A, Saijo E, Metrick MA, Newell K, Sigurdson CJ, Zanusso G, et al. Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease. Acta Neuropathol (Berl). 2019;137:585–98.PubMedCrossRef
17.
Manca M, Standke HG, Browne DF, Huntley ML, Thomas OR, Orrú CD, et al. Tau seeds occur before earliest Alzheimer’s changes and are prevalent across neurodegenerative diseases. Acta Neuropathol (Berl). 2023;146:31–50.PubMedCrossRef
18.
Saijo E, Ghetti B, Zanusso G, Oblak A, Furman JL, Diamond MI, et al. Ultrasensitive and selective detection of 3-repeat tau seeding activity in pick disease brain and cerebrospinal fluid. Acta Neuropathol (Berl). 2017;133:751–65.PubMedCrossRef
19.
Saijo E, Groveman BR, Kraus A, Metrick M, Orrù CD, Hughson AG, et al. Ultrasensitive RT-QuIC seed amplification assays for Disease-Associated tau, α-Synuclein, and Prion aggregates. Methods Mol Biol Clifton NJ. 2019;1873:19–37.CrossRef
20.
Wu L, Wang Z, Lad S, Gilyazova N, Dougharty DT, Marcus M, et al. Selective detection of misfolded tau from Postmortem Alzheimer’s Disease brains. Front Aging Neurosci. 2022;14: 945875.PubMedPubMedCentralCrossRef
21.
Becker B, Brinkmalm A, Burmann BM, Perkinton M, Ashton NJ, Fox NC, et al. Tau protein profiling in tauopathies: a human brain study. Mol Neurodegener. 2024;19:54–79.PubMedPubMedCentralCrossRef
22.
Wu L, Madhavan SS, Tan C, Xu B. Hexameric aggregation nucleation core sequences and diversity of pathogenic tau strains. Pathog Basel Switz. 2022;11:1559.CrossRef
23.
Chin KS, Churilov L, Doré V, Villemagne VL, Rowe CC, Yassi N, et al. Tau in dementia with Lewy bodies. Aust N Z J Psychiatry. 2023;58:175–82.PubMedCrossRef
24.
Hall B, Mak E, Cervenka S, Aigbirhio FI, Rowe JB, O’Brien JT. In vivo tau PET imaging in dementia: pathophysiology, radiotracer quantification, and a systematic review of clinical findings. Ageing Res Rev. 2017;36:50–63.PubMedCrossRef
25.
Nagaishi M, Yokoo H, Nakazato Y. Tau-positive glial cytoplasmic granules in multiple system atrophy. Neuropathol off J Jpn Soc Neuropathol. 2011;31:299–305.CrossRef
26.
Rong Z, Shen F, Wang Y, Sun L, Wu J, Zhang H, et al. Phosphorylated α-synuclein and phosphorylated tau-protein in sural nerves may contribute to differentiate Parkinson’s disease from multiple system atrophy and progressive supranuclear paralysis. Neurosci Lett. 2021;756:135964.PubMedCrossRef
27.
Vacchi E, Lazzarini E, Pinton S, Chiaro G, Disanto G, Marchi F, et al. Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies. Brain J Neurol. 2022;145:2755–68.CrossRef
28.
van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in Early Alzheimer’s Disease. N Engl J Med. 2023;388:9–21.PubMedCrossRef
29.
Angioni D, Hansson O, Bateman RJ, Rabe C, Toloue M, Braunstein JB, et al. Can we use blood biomarkers as Entry Criteria and for Monitoring Drug Treatment effects in clinical trials? A report from the EU/US CTAD Task Force. J Prev Alzheimers Dis. 2023;10:418–25.PubMed
30.
Knopman DS, Amieva H, Petersen RC, Chételat G, Holtzman DM, Hyman BT, et al. Alzheimer disease. Nat Rev Dis Primer. 2021;7:33.CrossRef
31.
Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement J Alzheimers Assoc. 2018;14:535–62.CrossRef
32.
NIA-AA Revised Clinical Guidelines for Alzheimer’sAAIC (//aaic.alz.org/nia-aa.asp.
33.
Boccalini C, Ribaldi F, Hristovska I, Arnone A, Peretti DE, Mu L et al. The impact of tau deposition and hypometabolism on cognitive impairment and longitudinal cognitive decline. Alzheimers Dement J Alzheimers Assoc. 2024;20:221–33.
34.
Orrú CD, Yuan J, Appleby BS, Li B, Li Y, Winner D, et al. Prion seeding activity and infectivity in skin samples from patients with sporadic Creutzfeldt-Jakob disease. Sci Transl Med. 2017;9:eaam7785.PubMedPubMedCentralCrossRef
35.
Wang Z, Manca M, Foutz A, Camacho MV, Raymond GJ, Race B, et al. Early preclinical detection of prions in the skin of prion-infected animals. Nat Commun. 2019;10:247.PubMedPubMedCentralCrossRef
36.
Bargar C, Wang W, Gunzler SA, LeFevre A, Wang Z, Lerner AJ, et al. Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol Commun. 2021;9:62.PubMedPubMedCentralCrossRef
37.
Donadio V, Wang Z, Incensi A, Rizzo G, Fileccia E, Vacchiano V, et al. In vivo diagnosis of synucleinopathies: a comparative study of skin biopsy and RT-QuIC. Neurology. 2021;96:e2513-2524.PubMedPubMedCentralCrossRef
38.
Kuzkina A, Bargar C, Schmitt D, Rößle J, Wang W, Schubert A-L, et al. Diagnostic value of skin RT-QuIC in Parkinson’s disease: a two-laboratory study. NPJ Park Dis. 2021;7:99.CrossRef
39.
Kuzkina A, Rößle J, Seger A, Panzer C, Kohl A, Maltese V, et al. Combining skin and olfactory α-synuclein seed amplification assays (SAA)-towards biomarker-driven phenotyping in synucleinopathies. NPJ Park Dis. 2023;9:79.CrossRef
40.
Chen D-D, Jiao L, Huang Y, Xiao K, Gao L-P, Chen C, et al. Application of α-Syn Real-Time Quaking-Induced Conversion for Brain and skin specimens of the Chinese patients with Parkinson’s Disease. Front Aging Neurosci. 2022;14:898516.PubMedPubMedCentralCrossRef
41.
Mammana A, Baiardi S, Quadalti C, Rossi M, Donadio V, Capellari S, et al. RT-QuIC detection of pathological α-Synuclein in skin punches of patients with Lewy Body Disease. Mov Disord off J Mov Disord Soc. 2021;36:2173–7.CrossRef
42.
Mammana A, Baiardi S, Rossi M, Franceschini A, Donadio V, Capellari S, et al. Detection of prions in skin punch biopsies of Creutzfeldt-Jakob disease patients. Ann Clin Transl Neurol. 2020;7:559–64.PubMedPubMedCentralCrossRef
43.
Xiao K, Yang X, Zhou W, Chen C, Shi Q, Dong X. Validation and application of skin RT-QuIC to patients in China with probable CJD. Pathog Basel Switz. 2021;10:1642.CrossRef
44.
Makrantonaki E, Brink TC, Zampeli V, Elewa RM, Mlody B, Hossini AM, et al. Identification of biomarkers of human skin ageing in both genders. Wnt signalling - a label of skin ageing? PLoS One. 2012;7:e50393.PubMedPubMedCentralCrossRef
45.
Miklossy J, Taddei K, Martins R, Escher G, Kraftsik R, Pillevuit O, et al. Alzheimer disease: curly fibers and tangles in organs other than brain. J Neuropathol Exp Neurol. 1999;58:803–14.PubMedCrossRef
46.
Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33:95–130.PubMedCrossRef
47.
Dugger BN, Hoffman BR, Scroggins A, Serrano GE, Adler CH, Shill HA, et al. Tau immunoreactivity in peripheral tissues of human aging and select tauopathies. Neurosci Lett. 2019;696:132–9.PubMedCrossRef
48.
Goedert M, Spillantini MG, Crowther RA. Cloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system. Proc Natl Acad Sci U S A. 1992;89:1983–7.PubMedPubMedCentralCrossRef
49.
Hamsafar Y, Chen Q, Borowsky AD, Beach TG, Serrano GE, Sue LI, et al. Biochemical analyses of tau and other neuronal markers in the submandibular gland and frontal cortex across stages of Alzheimer disease. Neurosci Lett. 2023;810: 137330.PubMedPubMedCentralCrossRef
50.
Akerman SC, Hossain S, Shobo A, Zhong Y, Jourdain R, Hancock MA, et al. Neurodegenerative disease-related proteins within the epidermal layer of the human skin. J Alzheimers Dis JAD. 2019;69:463–78.PubMedCrossRef
51.
Dugger BN, Whiteside CM, Maarouf CL, Walker DG, Beach TG, Sue LI, et al. The Presence of Select Tau species in Human Peripheral tissues and their relation to Alzheimer’s Disease. J Alzheimers Dis JAD. 2016;51:345–56.PubMedCrossRef
52.
Rodriguez-Leyva I, Chi-Ahumada E, Calderon A, Laura A, Verónica M-M. E S, Presence of phosphorylated tau protein in the skin of alzheimer´s disease patients. J Mol Biomark Diagn. 2015;S6:005.
53.
Iranzo A, Mammana A, Muñoz-Lopetegi A, Dellavalle S, Mayà G, Rossi M, et al. Misfolded α-Synuclein Assessment in the skin and CSF by RT-QuIC in isolated REM sleep behavior disorder. Neurology. 2023;100:e1944-54.PubMedPubMedCentralCrossRef
54.
Manne S, Kondru N, Jin H, Anantharam V, Huang X, Kanthasamy A, et al. α-Synuclein real-time quaking-induced conversion in the submandibular glands of Parkinson’s disease patients. Mov Disord off J Mov Disord Soc. 2020;35:268–78.CrossRef
55.
Zhang W, Orrú CD, Foutz A, Ding M, Yuan J, Shah SZA, et al. Large-scale validation of skin prion seeding activity as a biomarker for diagnosis of prion diseases. Acta Neuropathol. 2024;147:17.PubMedCrossRef
56.
Altamirano-Bustamante MM, Altamirano-Bustamante NF, Larralde-Laborde M, Lara-Martínez R, Leyva-García E, Garrido-Magaña E, et al. Unpacking the aggregation-oligomerization-fibrillization process of naturally-occurring hIAPP amyloid oligomers isolated directly from sera of children with obesity or diabetes mellitus. Sci Rep. 2019;9:18465.PubMedPubMedCentralCrossRef
57.
Bittar A, Bhatt N, Hasan TF, Montalbano M, Puangmalai N, McAllen S, et al. Neurotoxic tau oligomers after single versus repetitive mild traumatic brain injury. Brain Commun. 2019;1:fcz004.PubMedPubMedCentralCrossRef
58.
Metrick MA, Ferreira N do, Saijo C, Kraus E, Newell A, Zanusso K. A single ultrasensitive assay for detection and discrimination of tau aggregates of Alzheimer and pick diseases. Acta Neuropathol Commun. 2020;8:22.PubMedPubMedCentralCrossRef
59.
Zou W-Q, Zheng J, Gray DM, Gambetti P, Chen SG. Antibody to DNA detects scrapie but not normal prion protein. Proc Natl Acad Sci U S A. 2004;101:1380–5.PubMedPubMedCentralCrossRef
60.
Chang E, Kuret J. Detection and quantification of tau aggregation using a membrane filter assay. Anal Biochem. 2008;373:330–6.PubMedCrossRef
61.
Zou WQ, Yang DS, Fraser PE, Cashman NR, Chakrabartty A. All or none fibrillogenesis of a prion peptide. Eur J Biochem. 2001;268:4885–91.PubMedCrossRef
Metadata
Title
Seeding activity of skin misfolded tau as a biomarker for tauopathies
Authors
Zerui Wang
Ling Wu
Maria Gerasimenko
Tricia Gilliland
Zahid Syed Ali Shah
Evalynn Lomax
Yirong Yang
Steven A. Gunzler
Vincenzo Donadio
Rocco Liguori
Bin Xu
Wen-Quan Zou
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2024
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-024-00781-1

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