Faculty Bibliography

Transthyretin (TTR) is a 55 kDA tetrameric protein synthesized by the liver and the choroid plexus that binds thyroxine and retinol-binding protein. More than fifty mutations have been identified in the TTR gene, the majority of them associated with hereditary amyloidosis.(1) This study reveals the first silent mutation on the TTR gene:Ala108. $$:

Tissue deposition of monoclonal immunoglobulin light chains is a serious complication in some patients with B cell proliferative disorders. The deposits are typically fibrillar and Congophilic in amyloid (AL) and non-fibrillar and Congophobic in light chain deposition disease (LCDD), and rarely coexist in the same patient. From post-mortem tissue of an individual with fibrillar and non-fibrillar kappa light chain deposits in different sites, we separately extracted and analysed biochemically and immunochemically the non-amyloid deposits from isolated glomeruli, the amyloid from isolated renal arteries and the amyloid from myocardium in which the only deposits were amyloid restricted to mural arteries. Western blotting analysis of both the extracted amyloid and the non-amyloid deposits demonstrated 25-kD bands immunoreactive with anti-kappa antibody, and the identity of the N-terminal amino acid sequences that belong to the variable region kappaIV light chain subgroup. This is the first human disease in which antigenically similar but morphologically different deposits have been separately biochemically analysed. We propose that combined LCDD and AL is an ideal human disease to study the relationships and the factors that influence the conversion of non-amyloidogenic to amyloidogenic conformations

The genetic associations with the pathological features of AD are diverse: A rapidly growing number of mutations in presenilin 1 and 2 on chromosomes 14 and 1, respectively, are found in many early-onset FAD patients (Lendon et al., 1997). In addition, beta PP mutations are found in a small percentage of early-onset FAD kindreds. The apoE4 allele on chromosome 19 is associated with the presence of the most common form of AD, sporadic AD (Wisniewski & Frangione, 1992; Namba et al., 1991). However, it is clear that other proteins are also involved in the pathogenesis of AD, since some early-onset FAD kindreds do not have linkage to PS1, PS2, apoE, or beta PP, while at least 50% of late-onset AD is unrelated to apoE. Other proteins which have been implicated in the formation of senile plaques, but so far are not known to have any genetic linkage to AD, include proteoglycans (Snow et al., 1987), apoA1 (Wisniewski et al., 1995a), alpha 1-antichymotrypsin (Abraham et al., 1988), HB-GAM (Wisniewski et al., 1996a), complement components (McGeer & Rogers, 1992), acetylcholinesterase (Friede, 1965), and NAC (Ueda et al., 1993). Which of these proteins will be the most important for the etiology of the most common form of AD, late-onset sporadic AD, remains an open question. Three of the genes which are now known to be linked to AD, including PS1, beta PP, and apoE, have been established immunohistochemically and biochemically to be components of senile plaques (see Fig. 1). This raises at least two possibilities: either each of these proteins is part of one pathway with A beta-related amyloid formation as a final causative pathogenic event or amyloid deposition in AD is a reactive process related to dysfunction of a number of different CNS proteins. Whether or not amyloid formation is directly causative in the pathogenesis of AD, current data suggest that new therapeutic approaches which may inhibit the aggregation and/or the conformational change of sA beta to A beta fibrils (Soto et al., 1996) have the greatest likelihood to make a significant impact on controlling amyloid accumulation in AD

Mutations in presenilin (PS)-1 and -2, located on chromosome 14 and 1 respectively, are the major association with early-onset familial Alzheimer's disease (FAD). FAD has also been linked to mutations in the amyloid beta precursor protein (beta PP), and the presence of the apolipoprotein E4 allele is a risk factor for late-onset AD. The role of PS in FAD and in sporadic AD is unclear. We previously reported the presence of a PS-1 carboxyl-terminal epitope in neuritic plaques (Wisniewski T, Palha JA, Ghiso J, Frangione B: S182 protein in Alzheimer's disease neuritic plaques. Lancet 1995, 346:1366). In the present study, we examined a number of biochemically different cerebral and systemic amyloidoses, finding the PS-1 carboxy epitope only in association with amyloid beta (A beta) lesions. We confirm the presence of this epitope ultrastructurally in neuritic plaques. In addition, biochemical and amino acid sequence data are presented for an association of the 18-kd carboxy fragment of PS-1 with neuritic plaques with a start at residue 300. Three of the proteins with linkage to AD have now been found as components of neuritic plaques. It remains to be determined whether all of these proteins are involved in the same or different pathological pathway(s) and which of these proteins is the most important for the common, late-onset form of AD

The invasive stages of the parasitic trematode Fasciola hepatica release proteinases into the medium in which they are maintained. In this study, we investigated the interaction of F. hepatica excretory/secretory (E/S) products and 2 cysteine proteinases (CL1 and CL2) purified from these products with extracellular matrix and basement membrane macromolecules. Fasciola hepatica E/S products contained collagenolytic activity on fibrillar types I and III collagen as well as basement membrane type IV collagen. CL1 and CL2 were capable of degrading acid-soluble type III and type IV collagen but not insoluble type I collagen. In contrast, neither the E/S products nor the purified CL1 and CL2 showed elastinolytic activity. Fibronectin and laminin were degraded by E/S products and by CL1 and CL2. Sequence analysis of fibronectin degradation products showed that the fragments obtained corresponded to complete biologically active domains. These results indicate that the cysteine proteinases secreted by F. hepatica may be involved in the process of tissue invasion by the parasite

The inheritance of the apolipoprotein (apo) E4 allele is an important risk factor for late-onset Alzheimer's disease (AD). A major component of the Alzheimer's disease neuritic plaques is amyloid beta (A beta). We previously identified apoE/A beta complexes within neuritic plaques (1). It was not known if this interaction takes place before or after A beta peptides become incorporated into neuritic plaques. To address this question we sought evidence of apoE complexes with brain soluble A beta peptides in AD and control patients. In addition, numerous proteins have been shown to bind A beta peptides in vitro. It is not know if any of these bind brain sA beta in vivo. We found evidence for the presence of apoE/dimeric sA beta complexes in the AD brain and could not detect complexes with other A beta peptide binding proteins. The binding of sA beta to apoE may be one factor influencing its clearance from the brain and/or its conformational state