Cytoskeletal pathology in familial cerebral amyloid angiopathy (British type) with non-neuritic amyloid plaque formation

Abstract

The histological features of familial cerebral amyloid angiopathy (British type) with non-neuritic amyloid plaque formation (FAB) include deposition of amyloid, (supposedly associated with the C-terminal fragments of both alpha- and beta-tubulin), in small cerebral and spinal arteries, hippocampal amyloid plaques and neurofibrillary tangles (NFTs) as well as ischaemic white matter changes. In the present study we report on the cytoskeletal pathology that occurs in association with FAB. Sections from the hippocampus and cerebellum of three cases from three unrelated families were stained with silver impregnation methods and antibodies to antigens including tau, neurofilaments, ubiquitin and glial fibrillary acidic protein. Electron microscopic examination of the hippocampus was carried out in one case. All hippocampal subregions contained large numbers of NFTs and neuropil threads (NT), which were stained with both phosphorylation-dependent and phosphorylation-independent tau antibodies and ultrastructurally were found to be composed of paired helical filaments (PHFs). Although the majority of the amyloid plaques were of the non-neuritic type, distended PHF-containing and tau-positive neurites were seen in close proximity of a minority of the hippocampal plaques. The perivascular amyloid deposits of the cerebellum contained numerous ubiquitin-positive granular elements similar to those seen in cerebellar A beta amyloid plaques in Alzheimer's disease. In FAB severe cytoskeletal pathology is present in areas most affected by amyloid plaque deposits, thus suggesting a localised neurotoxic effect of the poorly characterised amyloidogenic peptide characteristic of this condition.

Familial Danish Dementia

“…In this sense, dimers (not monomers) of A␤ molecules were retrieved in co-immunoprecipitation experiments from tissue extracts and A␤-(1-42) and A␤-(4 -42) bound to ADan dimers and higher oligomers (not monomers) in ligand blot analysis, suggesting conformational specificity. It is important to note that A␤ was detected in neither parenchymal nor vascular ABri deposits in FBD (15,16) nor identified as an A␤ ligand in the ligand blot analysis shown in Fig. 7 despite being ABri and ADan molecules identical in their 22 N-terminal residues.…”

“…This early onset disorder, clinically characterized by progressive dementia, cerebellar ataxia, and spastic paraparesis, was first described by Worster-Drought et al (1933) as a familial presenile dementia with spastic paralysis (10 -13). The neuropathology of FBD is remarkably similar to that of FDD and AD, particularly in regard to the presence of neurofibrillary tangles ultrastructurally composed of classical paired helical filaments (14,15). As in FDD, the stop to Arg point mutation in FBD also eliminates the BRI2 stop codon and generates a longer than normal precursor ABriPP.…”

“…FBD amyloid deposits in the form of cerebral amyloid angiopathy, preamyloid lesions, and amyloid plaques are composed of ABri, an amyloid subunit that is also generated by furin proteolytic processing and shares 100% identity with ADan in its first 22 amino acids but that is completely different in its 12 C-terminal residues (6). Interestingly and despite the similarities between FDD and FBD, detailed immunohistochemical studies never found A␤ co-localized with ABri deposits (15,16).…”

MICAL-1 Is a Negative Regulator of MST-NDR Kinase Signaling and Apoptosis

“…26,27 This autosomal dominant disease is characterized by progressive spastic tetraparesis, cerebellar signs, and dementia in the fifth decade. [24][25][26] Neuropathologic findings include severe cerebral amyloid angiopathy, neurofibrillary tangles, and non-neuritic amyloid plaques of varying size.…”

The Familial British Dementia Mutation Promotes Formation of Neurotoxic Cystine Cross-linked Amyloid Bri (ABri) Oligomers

“…Although the Bri peptide is not known to be amyloidogenic (9,10), the ABri peptide is found in perivascular and parenchymal deposits in the brain of affected individuals (2). In addition to widespread amyloidosis, neurofibrillary tangles composed of hyperphosphorylated Tau protein are an invariant feature of this disease (11). Thus, the neuropathological presentation of FDB is highly similar to that seen in Alzheimer disease (AD); indeed, even the phosphorylation sites found on neurofibrillary tangles in FBD brain are the same as those present in AD (12).…”