Faculty Bibliography

ABETA is the main component of amyloid deposits in Alzheimers disease. A soluble form (sABETA) identical to the deposited ABETA is found in biological fluids and has the ability to cross the blood-brain barrier. The primary structure of ABETA and sABETA are indistinguishable and it is not clear whether sABETA reflects systemic production, brain clearance, or both. The pharmacokinetic parameters of synthetic soluble ABETA40 and ABETA42 species labeled with 125I or 125I-tyramine cellobiose were studied. Blood was drawn at different time points after a single dose of intravenous bolus-injection of the ABETA peptides to assess the distribution and elimination phases. Tissues were harvested at the end the experiment to determine organ uptake. The liver was found to be the major organ responsible for the clearance (>60%). Liver perfusion with collagenase followed by cell fractionation demonstrated that hepatocytes uptake >87% of the peptides while only 2% was found associated with Kupffer cells. (125I)-tyramine cellobiose ABETAwas also present in the gallbladder and small intestine, pointing to the biliary excretion as one of the clearance mechanisms. TCA-precipitable counts in plasma decreased exponentially shortly after the i.v. injection, suggesting that hydrolysis/enzymatic degradation are also important. Less than 15% biotransformation occurs via conjugation to plasma proteins under the conditions tested. The findings indicate that the liver plays a major role in the catabolism of sABETA, an issue to be considered in view of the current attempts to use synthetic homologues for therapeutic use

Familial Danish Dementia (FDD) is an early onset autosomal dominant disorder characterized by cataracts, deafness, progressive ataxia and dementia. Cerebral ADan amyloid and pre-amyloid deposits as well as NFTs in the hippocampus are the main neuropathological features of the disease. Surprisingly, Abeta was also found co-deposited in the amyloid lesions. We have biochemically characterized by immunoprecipitation, mass spectrometry, amino acid sequence and/or immunoblot analysis the ADan/Abeta species found in amyloid and pre-amyloid lesions in FDD brain and investigated the presence of soluble ADan and Abeta in plasma from carriers of the disease. ADan was composed by a mixture of full-length and C-terminal truncated species bearing N-terminal pyroglutamate (4044.6 Da). Abeta was mainly 1-42 and 4-42. Plasma soluble ADan contained N-terminal glutamate (4062.6 Da). The difference of 18 mass units accounts for the loss of one molecule of water. The conversion glutamate-pyroglutamate is chemically irreversible, indicating that sADan does not represent ADan being cleared from the brain amyloid but rather from soluble unmodified sADan species systemically produced and/or transported from the brain soluble pool. Thus, patients with FDD have two different types of amyloid molecules deposited in the brain and their respective soluble precursors are present in biological fluids. The significance of these unusual findings will be discussed

Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing different genetic defects, namely a Stop-to-Arg mutation in FBD and a ten-nucleotide duplication-insertion immediately before the stop codon in FDD. Both de novo created amyloid peptides have the same length (34 amino acids) and the same post-translational modification (pyroglutamate) at their N-terminus. Neurofibrillary tangles containing the classical paired helical filaments as well as neuritic components in many instances co-localize with the amyloid deposits. In both disorders, the pattern of hyperphosphorylated tau immunoreactivity is almost indistinguishable from that seen in Alzheimer's disease. These issues argue for the primary importance of the amyloid deposits in the mechanism(s) of neuronal cell loss. We propose FBD and FDD, the chromosome 13 dementia syndromes, as models to study the molecular basis of neurofibrillary degeneration, cell death and amyloid formation in the brain

Familial British dementia (FBD) is an early onset inherited disorder that, like familial Alzheimer's disease (FAD), is characterized by progressive dementia, amyloid deposition in the brain, and neurofibrillary degeneration of limbic neurons. The primary structure of the amyloid subunit (ABri) extracted from FBD brain tissues (Vidal, R., Frangione, B., Rostagno, A., Mead, S., Revesz, T., Plant, G., and Ghiso, J. (1999) Nature 399, 776-781) is entirely different and unrelated to any previously known amyloid protein. Patients with FBD have a single nucleotide substitution at codon 267 in the BRI2 gene, resulting in an arginine replacing the stop codon and a longer open reading frame of 277 amino acids instead of 266. The ABri peptide comprises the 34 C-terminal residues of the mutated precursor ABriPP-277 and is generated via furin-like proteolytic processing. Here we report that carriers of the Stop-to-Arg mutation have a soluble form of the amyloid peptide (sABri) in the circulation with an estimated concentration in the range of 20 ng/ml, several fold higher than that of soluble Abeta. In addition, ABri species identical to those identified in the brain were also found as fibrillar components of amyloid deposits predominantly in the blood vessels of several peripheral tissues, including pancreas and myocardium. We hypothesize that the high concentration of the soluble de novo created amyloidogenic peptide and/or the insufficient tissue clearance are the main causative factors for the formation of amyloid deposits outside the brain. Thus, FBD constitutes the first documented cerebral amyloidosis associated with neurodegeneration and dementia in which the amyloid deposition is also systemic

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