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.

Keywords: Alzheimer disease; Amyloid-β; Dura mater; Iatrogenic Creutzfeldt-Jakob disease; Prion; Propagon.

Fig. 1

Neuropathology of iCJD cases. Mild to moderate spongiform change in the HE staining (a, d) associated with diffuse/synaptic PrP immunoreactivity (b, e) and focal tau immunoreactive neuritic profiles (c, f indicated by arrows, a representative one is enlarged in right upper inset) in case iCJD-1 (a–c) and iCJD-2 (d–f). The same mature plaque with a corona in iCJD-2 as seen in immunostaining for Aβ (g), Bielschowsky (h), AT8 (i arrows indicate small neuritic profiles as seen in CJD cases but not around the mature plaque), HE (j arrowhead) and Congo staining (k arrowhead indicates the plaque as seen under polarized light). Bielschowsky staining (l, m) of two mature plaques lacking tau immunoreactivity close to each other in iCJD-2. Immunostaining for Aβ (n) and ubiquitin (o) in the same cortical regions close to the dura transplant in iCJD-1. Immunostaining for AβPP in frontal white matter in iCJD-1 (p) and iCJD-2 (q). Immunostaining for HLA-DR (microgliosis) in the frontal cortex (r) and white matter (s) in iCJD-1. The bar in image “a” represents 100 μm for a–f, r, s; 40 μm for g–m; and 60 μm for n–q

Fig. 2

Aβ immunoreactivity in iCJD-1. Immunostaining using the 6F/3D Aβ antibody (a, b, f, g, i–m, p–s), the 4G8 Aβ antibody (c, h), anti-Aβ_1–40 (e, n), and anti-Aβ_1–42 (d, o) demonstrated widespread immunoreactivity in the lesion area (a upper part enlarged in b–e); radiating deposits in the cortex (f) and white matter (g, h); focal deposits with columnar alignment perpendicular to the surface of the cortex (i–l); in a dilated vein (m), as immunostaining of plaques (n, o); and as dural deposits (p–s). The right upper inset in p is the enlargement of the area indicated by an arrowhead; r and s are enlargements of areas indicated by arrow and arrowhead in q, respectively. The bar in image “a” represents 150 μm for a, f, l, m–o; 60 μm for b–e; 40 μm for g, h, j, k; 100 μm for i, p, q and 15 μm for r, s

Fig. 3

Aβ immunoreactivity in iCJD-2. Immunostaining using the 6F/3D Aβ antibody (a–i) representing cerebral amyloid angiopathy (a), perivascular cored plaque (b upper right inset is the enlarged image of the vessel below the letter “b”), single area with subpial deposits (c including minicored plaques indicated by an arrowhead and as enlarged in the right upper inset); columnar alignment of plaques in the cortex (d indicated by a row of arrowheads; the surface of the cortex is labeled by a dashed line); lack of immunoreactivity in the host dura mater (e) and amorphous Aβ depositions in the graft dura mater (f–i; h and i is the enlargement of the areas indicated by an arrow and arrowhead in g, respectively). The bar in image “a” represents 150 μm for a; 40 μm for b, f; 100 μm for c, d, e, g; 15 μm for h, i

Fig. 4

Aβ in the dura mater in the aging brain. Image a–m represents dura mater samples from a representative patient as visualized by 4G8 (a–c; in c using enhanced PK treatment of the sections), 6F/3D Aβ antibody (d–g; insets in d and e represent immunostaining for collagen IV; f and g are enlargements of the areas indicated by asterisk in d and e, respectively), Aβ_1–40 (h, j), Aβ_1–42 (i, k) and van Gieson elastica (l, m). Further representative cases are shown using immunostaining for Aβ_1–40 (n), Aβ_1–42 (o), Congo staining under polarized light (p deposit in the connective tissue, q angiopathy), and 6F/3D (r–t; areas indicated with asterisk enlarged in the right upper inset; in t using enhanced PK-pretreatment). The bar in image “a” represents 20 μm for c, f, g, n, p, q, t; 40 μm for a, b, d, e, o, r, and s; and 80 μm for h–m