Modeling familial British and Danish dementia

Abstract

Familial British dementia (FBD) and familial Danish dementia (FDD) are two autosomal dominant neurodegenerative diseases caused by mutations in the BRI ( 2 ) gene. FBD and FDD are characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal amyloid deposition, and neurofibrillary tangles. Transgenic mice expressing wild-type and mutant forms of the BRI(2) protein, Bri ( 2 ) knock-in mutant mice, and Bri ( 2 ) gene knock-out mice have been developed. Transgenic mice expressing a human FDD-mutated form of the BRI ( 2 ) gene have partially reproduced the neuropathological lesions observed in FDD. These mice develop extensive CAA, parenchymal amyloid deposition, and neuroinflammation in the central nervous system. These animal models allow the study of the molecular mechanism(s) underlying the neuronal dysfunction in these diseases and allow the development of potential therapeutic approaches for these and related neurodegenerative conditions. In this review, a comprehensive account of the advances in the development of animal models for FBD and FDD and of their relevance to the study of Alzheimer disease is presented.

Fig. 1

Schematic diagram of wild-type and mutated forms of the type-II transmembrane protein BRI₂ as originally proposed by Vidal et al. (2004). a Processing by pro-protein convertases (PCs) releases a 23 amino acid peptide (Bri₂-23). Processing by ADAM10 in the ectodomain of BRI₂ releases the BRICHOS domain and an N-terminal fragment (NTF). Further processing of the membrane bound fragment by SPPL2a/SPPL2b releases an intracellular domain (ICD) and a secreted low molecular weight C-terminal peptide (C). Disulfide bonded loops in the BRICHOS domain and in the carboxy-terminus of BRI₂ are indicated. b Processing by PCs of the mutated precursor proteins releases the 34 amino acid ABri and ADan peptides

Fig. 2

ADan deposition in the cerebral cortex. a All cerebral cortical layers of Tg-FDD mice show ThS-fluorescent amyloid deposition. b Amyloid deposits were immunoreactive with anti-ADan antibodies (Ab 1700), which also stained the subpial region of the cerebral cortex and diffuse parenchymal deposits. Sections were from a 21 month-old Tg-FDD mice. Staining with ThS (a). Immunohistochemistry using Ab 1700 was done as described (Vidal et al. 2009) (b). Scale bars a, b 200 μm

Fig. 3

Vascular and parenchymal ADan deposition in the hippocampus. a Amyloid deposition was observed throughout the hippocampal formation of Tg-FDD mice by ThS. Fluorescent small, punctate deposits, ~3 μm in diameter were also observed. b ADan-immunopositive structures outlined the hippocampus. ADan was found in the walls of large and medium size vessels and in the walls of vessels of the hippocampal fissure. Sections were from a 21-month-old Tg-FDD mice. Staining with ThS (a). Immunohistochemistry using Ab 1700 (b, c). Scale bars a 100 μm, b, c 200 μm

Fig. 4

ADan deposition in Cerebellar leptomeninges. a ADan deposition was observed in pial (leptomeningeal) vessels of the cerebellum of Tg-FDD mice. b Antibodies against ADan immunolabel leptomeningeal and cortical blood vessels, and the subpial region of the cerebellar cortex of Tg-FDD mice. Sections were from a 21-month-old Tg-FDD mice. Staining with ThS (a). Immunohistochemistry using Ab 1700 (b). Scale bars a 100 μm, b 200 μm

Fig. 5

Ultrastructural analysis of cerebral vascular ADan deposition in Tg-FDD mice. a Amyloid deposits in leptomeningeal vessels of the cerebellum were observed within the vessel wall or appeared as circumscribed deposits with radially oriented fibrils. b Abnormal thickening of the basal lamina as well as degeneration and death of endothelial cells was observed in hippocampal vessel walls, in some cases with penetrance of amyloid into the vascular basement membrane. Transmission electron microscopy (TEM) of a 18-month-old Tg-FDD mouse. Amyloid (A), vessel lumen (L), dystrophic neurites (DN) and astrocytic processes (AS) were identified

Fig. 6

Ultrastructure of hippocampal parenchymal amyloid deposits. a Bundles of fibrillar amyloid are seen within microglial cells. Swollen astroglial processes containing glial filaments are seen in close proximity to the amyloid deposit as well as degenerating neuronal processes and dystrophyc neurites. b Neurons adjacent to amyloid deposits, particularly in the hippocampus, showed morphological evidence of degeneration, and often ultrastructural features of cellular death. Transmission electron microscopy (TEM) of an 18-month-old Tg-FDD mouse. Amyloid (A), dystrophic neurites (DN), microglia (M), neurons (N), and astrocytic processes (AS) were identified

Fig. 7

Tg-Tau × Tg-FDD mice. a Phosphorylated tau, b GFAP-positive reactive astrocytes, and c keratan sulfate-positive activated microglia in the hippocampus and motor cortex of Tg-Tau × Tg-FDD mice. d Antibodies against ADan immunolabel hippocampal blood vessels and perivascular deposits in Tg-Tau × Tg-FDD mice. Sections were from a 12-month-old homozygous Tg-Tau × Tg-FDD mice. Immunohistochemistry using AT8 (a), anti-GFAP (b), 5D4 (c), and anti-ADan (1700) (d). Scale bars a–c 200 μm, d 100 μm