Dura mater is a potential source of Aβ seeds

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.

Can Creutzfeldt-Jakob disease unravel the mysteries of Alzheimer?

“…In these cases the subpial cortical area near to the traumatic lesion and the surgical intervention showed tissue damage. Strikingly, the morphological spectrum of Aβ depositions in these 2 cases was much more limited and different as compared to that seen in AD, other forms of CJD, traumatic brain injury, and cognitively normal individuals 28 . Instead of diffuse plaques, we observed focal deposits and congophilic cored plaques with and without a neuritic corona.…”

“…Dystrophic neurites around the plaques accumulated ubiquitin but not hyperphosphorylated tau. We observed clusters away from the lesion site or columnar alignment of Aβ plaques close to the lesion 28 . We also emphasized that NFTs were completely lacking even in subcortical areas where it may be seen in young individuals 11 .…”

“…Our observations on 84 dura mater samples obtained in a longitudinal community-based aging study provided evidence for the first time that the dura mater may harbor Aβ deposits in the form of CAA or amorphous aggregates. Furthermore, this study is the only one, which compared cadaveric and host dura mater samples and demonstrated the presence of Aβ only in the cadaveric dura mater sample in addition to the brain tissue of the host 28 . Importantly, these cases are the youngest reported with iatrogenic CJD and Aβ deposition, and we excluded genetic predisposing factors ( APOE, APPP, PSEN 1, 2 ).…”

“…Moreover, it was still not known whether 1) the cadaveric tissue used in these iatrogenic CJD cases exhibit Aβ depositions, and 2) there are any distinctive features of brain pathology in these cases. To answer these questions, we performed an additional study on 2 cases 28 . We used 4 anti-Aβ antibodies (clones 6F/3D, 4G8, anti-Aβ 1–40 , and anti-Aβ 1–42 ) to provide unequivocal results and not misinterpret non-specific stainings.…”

Significant association of cadaveric dura mater grafting with subpial Aβ deposition and meningeal amyloid angiopathy

“…Recently, the possibility of human-to-human transmission of cerebral β-amyloidosis has been suggested in autopsy studies of patients with iatrogenic Creutzfeldt-Jakob disease (CJD) associated with human growth hormone injection or dura mater graft [1,3,4]. To evaluate the possibility of iatrogenic transmission of cerebral β-amyloidosis in humans via cadaveric dura mater graft, we performed immunohistochemical studies on 16 patients with dura mater graft-associated CJD (dCJD) and 21 patients with sporadic CJD (sCJD) using antibodies against prion protein (PrP), amyloid β-protein (Aβ), phosphorylated tau, phosphorylated α-synuclein, and phosphorylated transactive response DNA-binding protein-43 (TDP-43) (see supplementary methods).…”