Regional distribution of amyloid-Bri deposition and its association with neurofibrillary degeneration in familial British dementia

Abstract

Familial British dementia (FBD), pathologically characterized by cerebral amyloid angiopathy (CAA), amyloid plaques, and neurofibrillary degeneration, is associated with a stop codon mutation in the BRI gene resulting in the production of an amyloidogenic fragment, amyloid-Bri (ABri). The aim of this study was to assess the distribution of ABri fibrillar and nonfibrillar lesions and their relationship to neurofibrillary pathology, astroglial and microglial response using immunohistochemistry, confocal microscopy, and immunoelectron microscopy in five cases of FBD. Abnormal tau was studied with immunoblotting. We present evidence that ABri is deposited throughout the central nervous system in blood vessels and parenchyma where both amyloid (fibrillar) and pre-amyloid (nonfibrillar) lesions are formed. Ultrastructurally amyloid lesions appear as bundles of fibrils recognized by an antibody raised against ABri, whereas Thioflavin S-negative diffuse deposits consist of amorphous electron-dense material with sparse, dispersed fibrils. In contrast to nonfibrillar lesions, fibrillar ABri is associated with a marked astrocytic and microglial response. Neurofibrillary tangles and neuropil threads occurring mainly in limbic structures, are found in areas affected by all types of ABri lesions whereas abnormal neurites are present around amyloid lesions. Immunoblotting for tau revealed a triplet electrophoretic migration pattern. Our observations confirm a close link between ABri deposition and neurodegeneration in FBD.

Figure 1.

A: Numerous Ab 338-positive structures outlining the anatomical regions of the hippocampus. B: Extensive Ab 338-positive structures in the cerebellar cortex. C: Large (arrowhead) and small (arrow) plaques in the (hippocampus) CA2 subregion. D: Diffuse deposits in the fusiform gyrus. E: An affected leptomeningeal vessel showing ABri deposition with enhanced staining of the periphery. F: Small parenchymal vessel with staining of the vessel wall and perivascular parenchyma. G: The Ab 338 staining pattern of the entorhinal cortex showing a bi-laminar appearance becoming united toward the transenthorhinal cortex (arrow). H: Ab 338-positive diffuse deposits in the parvopyramidal cell clusters (arrow) of the pre- and parasubiculum. I: Membranous staining of a pyramidal neuron in CA1 (arrow). J: An extracellular neurofibrillary tangle labeled by Ab 338 partly incorporated into a small plaque (arrow). K: Tau immunohistochemistry in the basal nucleus of the amygdala showing NFT (double arrow), NTs (arrow), and ANs (arrowhead). Ab 338 immunohistochemistry (A–J) and AT8 immunohistochemistry (K). GCL, granular cell layer of the dentate fascia. Original magnifications: ×6 (A); ×8 (G and H); ×30 (B); ×70 (C and D); ×130 (E, F, and K); ×200 (I and J).

Figure 2.

Confocal images. A, B, and C: There is a good overlap between Thioflavin S (green) and Ab 338 (red) staining of plaques as demonstrated in the combined image (C). However a small area is Thioflavin S-negative suggesting nonfibrillary protein (arrow). D, E, and F: Hippocampal blood vessel with perivascular Ab 338 staining, which is Thioflavin S-negative (arrow). G, H, and I: Hippocampal blood vessel with a good overlap between Thioflavin S and Ab 338 indicating fibrillar ABri. J and K: Ab 338 (green) and CD68 (red) double immunohistochemistry showing a marked microglial response around hippocampal amyloid plaques (J), but sparse reaction in the entorhinal cortex where the protein is predominantly nonfibrillar (K). L and M: Ab 338 (green) and GFAP (red) double immunohistochemistry showing a similar pattern of astrocytic reaction in the same areas; on M arrowhead points to an astrocytic process. N and O: Thioflavin S and Ab 338 double-staining shows a nonfibrillar perineuronal staining pattern (arrow) in the inferior olive (N), anterior horn of the sacral cord (O). There is an amyloid plaque in the inferior olive (double arrow). n = neuron. Original magnifications: ×20 (A–I), ×10 (J and L), and ×40 (K, M, N, and O).

Figure 3.

Ab 338 immunoelectron microscopy. B: Bundles of labeled fibrils in a hippocampal plaque. An astrocytic process (a) is unlabeled. Insert A showing labeled fibrils with high magnification. C: Amorphous electron-dense material together with sparse fibrils is decorated with Ab 338 in a Thioflavin S-negative area of temporal neocortex. D: Small vessel showing labeling of the basal lamina (b), which is focally disrupted by amyloid fibrils. E: A vessel showing extensive deposition of labeled fibrils in the basal lamina. D and E: Endothelial cells (e) are unlabeled. Original magnifications: ×16,000 (A); ×6,600 (B); ×10,000 (C); ×8,300 (D); and ×13,000 (E).

Figure 4.

Tau immunoblots in AD (lane 1) and FBD (lane 2) cases using the PHF1 antibody.