Faculty Bibliography

The term cerebral amyloid angiopathy (CAA) refers to the specific deposition of amyloid fibrils in the walls of leptomeningeal and cortical arteries, arterioles and, although less frequently in capillaries and veins. It is commonly associated with Alzheimers disease, Down's syndrome and normal aging, as well as with a variety of familial conditions related to stroke and/or dementia: hereditary cerebral hemorrhage with amyloidosis of Icelandic type (HCHWA-I), various inherited disorders linked to Abeta mutants (including the Dutch variant of HCHWA), and the recently described chromosome 13 familial dementia in British and Danish kindreds. This review focuses on four different types of hereditary CAA, emphasizing the notion that CAA is not only related to stroke but also to neurodegeneration and dementia of the Alzheimer's type

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

Familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the CNS and neurodegeneration. Amyloids ABri and ADan are C-terminal degradation products of the same precursor BriPP codified by the chromosome 13 BRI2 gene bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide insertion before the stop codon in FDD. Both de novo created amyloid peptides are 34 amino acids long, share 100% identity of the first 22 residues and pyroglutamate at their N-terminus. Neuritic components and NFTs containing PHF co-localize with the amyloid deposits in both disorders and the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in AD. To explore the role of inflammatory factors in these familial disorders, complement activation was assessed via immunohistochemistry, hemolytic assays and ELISA. Components and activation products (i.e. C1q, iC3b, C3d, C4d, C5b-9) were found to co-localize with plaques and vascular deposits in both diseases, suggesting in situ activation. ABri and ADan synthetic peptides activated the classical pathway in vitro and resulted in the formation of the activation products iC3b, C4d and SC5b-9 at levels comparable to those generated by Abeta42. The ability of ABri and ADan to trigger the complement cascade in vitro together with the presence of complement proteins and activation products as integral components of parenchymal and vascular amyloid deposits suggest that, as indicated in AD, the complement system may contribute to the mechanism of neurodegeneration leading to dementia

Apolipoprotein J (clusterin) is a ubiquitous multifunctional glycoprotein capable of interacting with a broad spectrum of molecules. In pathological conditions, it is an amyloid associated protein, co-localizing with fibrillar deposits in systemic and localized amyloid disorders. In Alzheimer's disease, the most frequent form of amyloidosis in humans and the major cause of dementia in the elderly, apoJ is present in amyloid plaques and cerebrovascular deposits but is rarely seen in NFT-containing neurons. ApoJ expression is up-regulated in a wide variety of insults and may represent a defense response against local damage to neurons. Four different mechanisms of action could be postulated to explain the role of apoJ as a neuroprotectant during cellular stress: (1) function as an anti-apoptotic signal, (2) protection against oxidative stress, (3) inhibition of the membrane attack complex of complement proteins locally activated as a result of inflammation, and (4) binding to hydrophobic regions of partially unfolded, stressed proteins, and therefore avoiding aggregation in a chaperone-like manner. This review focuses on the association of apoJ in biological fluids with Alzheimer's soluble Abeta. This interaction prevents Abeta aggregation and fibrillization and modulates its blood-brain barrier transport at the cerebrovascular endothelium.

Amyloidosis is a disorder of protein conformation leading to aggregation. The term defines a diverse group of proteins normally present in body fluids as soluble precursors that can be deposited as insoluble amyloid fibrils in different tissues producing organ dysfunction and cell death. These fibrils are composed of self-assembled, low molecular weight mass peptides adopting beta-pleated sheet structure, the conformation responsible for their physicochemical properties and tinctoreal characteristics. So far, 20 different proteins have been identified as subunits of amyloid fibrils (Westermark et al., 1999). Collectively, they are products of normal genes; however, several amyloid precursors contain abnormal amino acid substitutions that can impose an unusual potential for self-aggregation. The molecular mass of the amyloid peptides is within the 4 to 30-kDa range, with heterogeneity at the amino- and carboxyl-terminal portions found in most amyloid proteins. Increased levels of amyloid precursors, either in the circulation or locally in sites of deposition, are usually the result of overexpression or defective clearance, or both. Of the 20 amyloid proteins identified, few of them are known to cause amyloid deposition in the central nervous system, which in turn results in cognitive deficits, dementia, stroke, cerebellar and extrapyramidal signs, or a combination of them

Familial British dementia (FBD) is an early-onset autosomal dominant disorder characterized by progressive cognitive impairment, spasticity, and cerebellar ataxia. Hippocampal neurofibrillar degeneration and widespread parenchymal and vascular amyloid deposits are the main neuropathological lesions. Amyloid fibrils are composed of a novel 34 amino acid subunit (ABri) with no sequence identity to any known amyloid molecule. The peptide derives from a larger precursor protein codified by a single gene BRI on chromosome 13. Affected family members have a single base substitution at the stop codon of the BRI gene that generates a longer open-reading frame resulting in a larger precursor protein. The release of the 34 C-terminal amino acids from the mutated precursor originates the ABri amyloid subunit. Our discovery of a new amyloid associated with the development of dementia supports the concept that amyloid peptides may be of primary importance in the initiation of neurodegeneration