Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica
Published in: Acta Neuropathologica 6/2016

Open Access 01-06-2016 | Original Paper

Dura mater is a potential source of Aβ seeds

Authors: Gabor G. Kovacs, Mirjam I. Lutz, Gerda Ricken, Thomas Ströbel, Romana Höftberger, Matthias Preusser, Günther Regelsberger, Selma Hönigschnabl, Angelika Reiner, Peter Fischer, Herbert Budka, Johannes A. Hainfellner

Published in: Acta Neuropathologica | Issue 6/2016

Login to get access

Abstract

Deposition of amyloid-β (Aβ) in the brain parenchyma and vessels is one of the hallmarks of Alzheimer disease (AD). Recent observations of Aβ deposition in iatrogenic Creutzfeldt-Jakob disease (iCJD) after dural grafting or treatment with pituitary extracts raised concerns whether Aβ is capable of transmitting disease as seen in prion diseases by the disease-associated prion protein. To address this issue, we re-sampled and re-evaluated archival material, including the grafted dura mater of two cases with iCJD (28 and 33-years-old) without mutations in the AβPP, PSEN1 and PSEN2 genes, and carrying ε3/ε3 alleles of the APOE gene. In addition, we evaluated 84 dura mater samples obtained at autopsy (mean age 84.9 ± 0.3) in the community-based VITA study for the presence of Aβ deposition. We show that the dura mater may harbor Aβ deposits (13 %) in the form of cerebral amyloid angiopathy or amorphous aggregates. In both iCJD cases, the grafted dura mater had accumulated Aβ. The morphology and distribution pattern of cerebral Aβ deposition together with the lack of tau pathology distinguishes the Aβ proteinopathy in iCJD from AD, from that seen in young individuals without cognitive decline carrying one or two APOE4 alleles, and from that related to traumatic brain injury. Our novel findings of Aβ deposits in the dura mater, including the grafted dura, and the distinct cerebral Aβ distribution in iCJD support the seeding properties of Aβ. However, in contrast to prion diseases, our study suggests that such Aβ seeding is unable to reproduce the full clinicopathological phenotype of AD.
Literature
1.
Aho L, Pikkarainen M, Hiltunen M, Leinonen V, Alafuzoff I (2010) Immunohistochemical visualization of amyloid-beta protein precursor and amyloid-beta in extra- and intracellular compartments in the human brain. J Alzheimers Dis 20:1015–1028PubMed
2.
Alafuzoff I, Thal DR, Arzberger T et al (2009) Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium. Acta Neuropathol 117:309–320CrossRefPubMedPubMedCentral
3.
Andres KH (1967) On the fine structure of the arachnoidea and dura mater of mammals. Z Zellforsch Mikrosk Anat 79:272–295CrossRefPubMed
4.
Aspelund A, Antila S, Proulx ST et al (2015) A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med 212:991–999CrossRefPubMedPubMedCentral
5.
Attems J, Jellinger K, Thal DR, Van Nostrand W (2011) Review: sporadic cerebral amyloid angiopathy. Neuropathol Appl Neurobiol 37:75–93CrossRefPubMed
6.
Bohl J, Storkel S, Steinmetz H (1989) Involvement of the central nervous system and its coverings in different forms of amyloidosis. Prog Clin Biol Res 317:1007–1019PubMed
7.
Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181CrossRefPubMed
8.
Braak H, Del Tredici K (2015) The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease. Brain 138:2814–2833CrossRefPubMed
9.
Brettschneider J, Del Tredici K, Lee VM, Trojanowski JQ (2015) Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci 16:109–120CrossRefPubMedPubMedCentral
10.
Carare RO, Hawkes CA, Jeffrey M, Kalaria RN, Weller RO (2013) Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol Appl Neurobiol 39:593–611CrossRefPubMed
11.
Chen XH, Johnson VE, Uryu K, Trojanowski JQ, Smith DH (2009) A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. Brain Pathol 19:214–223CrossRefPubMedPubMedCentral
12.
Cupidi C, Capobianco R, Goffredo D et al (2010) Neocortical variation of Abeta load in fully expressed, pure Alzheimer’s disease. J Alzheimers Dis 19:57–68PubMed
13.
Delaere P, Duyckaerts C, He Y, Piette F, Hauw JJ (1991) Subtypes and differential laminar distributions of beta A4 deposits in Alzheimer’s disease: relationship with the intellectual status of 26 cases. Acta Neuropathol 81:328–335CrossRefPubMed
14.
Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36CrossRefPubMed
15.
Eisele YS, Duyckaerts C (2016) Propagation of Aβ pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol 131:5–25CrossRefPubMed
16.
Fischer P, Jungwirth S, Krampla W, et al. (2002) Vienna Transdanube Aging “VITA”: study design, recruitment strategies and level of participation. J Neural Transm Suppl 62:105–116CrossRefPubMed
17.
Földi M, Csanda E, Simon M et al (1968) Lymphogenic haemangiopathy. “Prelymphatic” pathways in the wall of cerebral and cervical blood vessels. Angiologica 5:250–262PubMed
18.
Frontzek K, Lutz MI, Aguzzi A, Kovacs GG, Budka H (2016) Amyloid-beta pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med Wkly 146:w14287PubMed
19.
Ghoshal N, Cali I, Perrin RJ et al (2009) Codistribution of amyloid beta plaques and spongiform degeneration in familial Creutzfeldt-Jakob disease with the E200K-129M haplotype. Arch Neurol 66:1240–1246CrossRefPubMedPubMedCentral
20.
Grinberg LT, Rub U, Ferretti RE et al (2009) The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer’s disease. A precocious onset? Neuropathol Appl Neurobiol 35:406–416CrossRefPubMed
21.
22.
Hixson JE, Vernier DT (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 31:545–548PubMed
23.
Horsburgh K, Cole GM, Yang F et al (2000) beta-amyloid (Abeta)42(43), abeta42, abeta40 and apoE immunostaining of plaques in fatal head injury. Neuropathol Appl Neurobiol 26:124–132CrossRefPubMed
24.
Irwin DJ, Abrams JY, Schonberger LB et al (2013) Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol 70:462–468CrossRefPubMedPubMedCentral
25.
Jaunmuktane Z, Mead S, Ellis M et al (2015) Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature 525:247–250CrossRefPubMed
26.
Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart W (2013) Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136:28–42CrossRefPubMedPubMedCentral
27.
Johnson VE, Stewart W, Smith DH (2010) Traumatic brain injury and amyloid-beta pathology: a link to Alzheimer’s disease? Nat Rev Neurosci 11:361–370PubMedPubMedCentral
28.
Johnson VE, Stewart W, Smith DH (2012) Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans. Brain Pathol 22:142–149CrossRefPubMedPubMedCentral
29.
30.
Kida S, Pantazis A, Weller RO (1993) CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol 19:480–488CrossRefPubMed
31.
32.
Kovacs GG, Budka H (2013) The spectrum of tau pathology in human prion disease. In: Zou W-Q, Gambetti P (eds) Prions and diseases. Springer, New York, pp 103–119CrossRef
33.
Kovacs GG, Horvath MC, Majtenyi K, Lutz MI, Hurd YL, Keller E (2015) Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions. Neurobiol Aging 36:3100–3107CrossRefPubMed
34.
Kovacs GG, Milenkovic I, Wohrer A et al (2013) Non-Alzheimer neurodegenerative pathologies and their combinations are more frequent than commonly believed in the elderly brain: a community-based autopsy series. Acta Neuropathol 126:365–384CrossRefPubMed
35.
Kovacs GG, Seguin J, Quadrio I et al (2011) Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy. Acta Neuropathol 121:39–57CrossRefPubMed
36.
Leclercq PD, Murray LS, Smith C, Graham DI, Nicoll JA, Gentleman SM (2005) Cerebral amyloid angiopathy in traumatic brain injury: association with apolipoprotein E genotype. J Neurol Neurosurg Psychiatry 76:229–233CrossRefPubMedPubMedCentral
37.
Lewis J, Dickson DW (2016) Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol 131:27–48CrossRefPubMed
38.
39.
McKee AC, Cairns NJ, Dickson DW et al (2016) The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol 131:75–86CrossRefPubMedPubMedCentral
40.
41.
42.
Metsaars WP, Hauw JJ, van Welsem ME, Duyckaerts C (2003) A grading system of Alzheimer disease lesions in neocortical areas. Neurobiol Aging 24:563–572CrossRefPubMed
43.
Murakami T, Ishiguro N, Higuchi K (2014) Transmission of systemic AA amyloidosis in animals. Vet Pathol 51:363–371CrossRefPubMed
44.
Parchi P, de Boni L, Saverioni D et al (2012) Consensus classification of human prion disease histotypes allows reliable identification of molecular subtypes: an inter-rater study among surveillance centres in Europe and USA. Acta Neuropathol 124:517–529CrossRefPubMedPubMedCentral
45.
Pletnikova O, Rudow GL, Hyde TM et al (2015) Alzheimer lesions in the autopsied brains of people 30 to 50 years of age. Cogn Behav Neurol 28:144–152CrossRefPubMed
46.
Preusser M, Ströbel T, Gelpi E et al (2006) Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting. J Neurol Neurosurg Psychiatry 77:413–416CrossRefPubMedPubMedCentral
47.
48.
Roland J, Bernard C, Bracard S et al (1987) Microvascularization of the intracranial dura mater. Surg Radiol Anat 9:43–49CrossRefPubMed
49.
50.
51.
Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H (2002) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293CrossRefPubMed
52.
Thal DR, Griffin WS, de Vos RA, Ghebremedhin E (2008) Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol 115:599–609CrossRefPubMed
53.
Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800CrossRefPubMed
54.
Tokuda T, Ikeda S, Yanagisawa N, Ihara Y, Glenner GG (1991) Re-examination of ex-boxers’ brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein. Acta Neuropathol 82:280–285CrossRefPubMed
55.
Uchihara T, Giasson BI (2016) Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol 131:49–73CrossRefPubMedPubMedCentral
56.
Uchihara T, Giasson BI, Paulus W (2016) Propagation of Abeta, tau and alpha-synuclein pathology between experimental models and human reality: prions, propagons and propaganda. Acta Neuropathol 131:1–3CrossRefPubMed
57.
Weller RO, Subash M, Preston SD, Mazanti I, Carare RO (2008) Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer’s disease. Brain Pathol 18:253–266CrossRefPubMed
Metadata
Title
Dura mater is a potential source of Aβ seeds
Authors
Gabor G. Kovacs
Mirjam I. Lutz
Gerda Ricken
Thomas Ströbel
Romana Höftberger
Matthias Preusser
Günther Regelsberger
Selma Hönigschnabl
Angelika Reiner
Peter Fischer
Herbert Budka
Johannes A. Hainfellner
Publication date
01-06-2016
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 6/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-016-1565-x

Other articles of this Issue 6/2016

Acta Neuropathologica 6/2016 Go to the issue

Original Paper

Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy

Original Paper

CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study

Consensus Paper

Risk stratification of childhood medulloblastoma in the molecular era: the current consensus

Original Paper

Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets

Original Paper

Methylation-based classification of benign and malignant peripheral nerve sheath tumors

Review

The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary