Biomedical subjects

G Multhaup

Publications and source records attributed to G Multhaup.

96 records · Page 6Linked to original sources

PubMed1985

The protein component of scrapie-associated fibrils is a glycosylated low molecular weight protein.

Scrapie-associated fibril protein (SAF-protein) extracted from infectious scrapie-associated fibrils (SAF) isolated from scrapie hamster brains is not infectious. SAF-protein is composed of various mol. wt. species of glycoproteins differing in carbohydrate content rather than amino acid composition. The N-linked carbohydrate chains represent approximately 40-60% of the mol. wt. of SAF-protein. The deglycosylated SAF-protein has a surprisingly low mol. wt. of approximately 7 kd, representing approximately 55 amino acid residues. This size and chemical analyses indicate that SAF-protein is an amyloid-type of protein. The simplest explanation for the available data is that SAF-polypeptide is very likely not to be part of the scrapie agent but that it is, like other amyloid proteins, derived from host-encoded proteins and not infectious. It is suggested that the infectivity of fractions rich in SAF is due to co-purification of scrapie virus and SAF caused by the high carbohydrate content of SAF-protein.

Amino Acid Sequence↗

PubMed1985

Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer's disease contain the same protein as the amyloid of plaque cores and blood vessels.

The protein component of Alzheimer's disease amyloid [neurofibrillary tangles (NFT), amyloid plaque core and congophilic angiopathy] is an aggregated polypeptide with a subunit mass of 4 kd (the A4 monomer). Based on the degree of N-terminal heterogeneity, the amyloid is first deposited in the neuron, and later in the extracellular space. Using antisera raised against synthetic peptides, we show that the N terminus of A4 (residues 1-11) contains an epitope for neurofibrillary tangles, and the inner region of the molecule (residues 11-23) contains an epitope for plaque cores and vascular amyloid. The non-protein component of the amyloid (aluminum silicate) may form the basis for the deposition or amplification (possible self-replication) of the aggregated amyloid protein. The amyloid of Alzheimer's disease is similar in subunit size, composition but not sequence to the scrapie-associated fibril and its constituent polypeptides. The sequence and composition of NFT are not homologous to those of any of the known components of normal neurofilaments.

Alzheimer Disease↗

PubMed1985

Amyloid plaque core protein in Alzheimer disease and Down syndrome.

We have purified and characterized the cerebral amyloid protein that forms the plaque core in Alzheimer disease and in aged individuals with Down syndrome. The protein consists of multimeric aggregates of a polypeptide of about 40 residues (4 kDa). The amino acid composition, molecular mass, and NH2-terminal sequence of this amyloid protein are almost identical to those described for the amyloid deposited in the congophilic angiopathy of Alzheimer disease and Down syndrome, but the plaque core proteins have ragged NH2 termini. The shared 4-kDa subunit indicates a common origin for the amyloids of the plaque core and of the congophilic angiopathy. There are superficial resemblances between the solubility characteristics of the plaque core and some of the properties of scrapie infectivity, but there are no similarities in amino acid sequences between the plaque core and scrapie polypeptides.

Alzheimer Disease↗

PubMedDate not supplied

Characterization of the high affinity heparin binding site of the Alzheimer's disease beta A4 amyloid precursor protein (APP) and its enhancement by zinc(II).

The Alzheimer's disease beta A4 amyloid precursor protein (APP) has been shown to be involved in a diverse set of biological activities including regulation of cell growth, neurite outgrowth and adhesiveness. The APP and amyloid protein precursor-like proteins (APLP1 and APLP2) belong to a superfamily of proteins that are probably functionally related. In order to characterize the cell adhesion properties of APP the brain specific isoform APP695 was purified and used to assess the binding to heparin, a structural and functional analogue of the glycosaminoglycan heparan sulfate. We show that APP binds in a time dependent and saturable manner to heparin. The salt concentration of 620 mM at which APP elutes from heparin Sepharose is greater than physiological. The apparent equilibrium constant for dissociation was determined to be 300 pM for APP binding to heparin Sepharose. A high affinity heparin binding site was identified within a region conserved in rodent and human APP, APLP1 and APLP2. This binding site was located between residues 316-337 of APP695 which is within the carbohydrate domain of APP. We also demonstrate an interaction between this heparin binding site and the zinc(II) binding site which is conserved in all members of the APP superfamily. We show by using an automated surface plasmon resonance biosensor (BIAcore, Pharmacia) that the affinity for heparin is increased two- to four-fold in the presence of micromolar zinc(II). The identification of zinc-enhanced binding of APP to heparan sulfate side chains of proteoglycans offers a molecular link between zinc(II), as a putative environmental toxin for Alzheimer's disease, and aggregation of amyloid beta A4 protein.

Alzheimer Disease↗

PubMedDate not supplied

The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor.

Alzheimer's disease is characterized by a widespread functional disturbance of the human brain. Fibrillar amyloid proteins are deposited inside neurons as neurofibrillary tangles and extracellularly as amyloid plaque cores and in blood vessels. The major protein subunit (A4) of the amyloid fibril of tangles, plaques and blood vessel deposits is an insoluble, highly aggregating small polypeptide of relative molecular mass 4,500. The same polypeptide is also deposited in the brains of aged individuals with trisomy 21 (Down's syndrome). We have argued previously that the A4 protein is of neuronal origin and is the cleavage product of a larger precursor protein. To identify this precursor, we have now isolated and sequenced an apparently full-length complementary DNA clone coding for the A4 polypeptide. The predicted precursor consists of 695 residues and contains features characteristic of glycosylated cell-surface receptors. This sequence, together with the localization of its gene on chromosome 21, suggests that the cerebral amyloid deposited in Alzheimer's disease and aged Down's syndrome is caused by aberrant catabolism of a cell-surface receptor.

Alzheimer Disease↗

PubMedDate not supplied

A vicious circle: role of oxidative stress, intraneuronal Abeta and Cu in Alzheimer's disease.

Recent evidence indicates that both intraneuronal Abeta and Cu are involved in the pathological processes in Alzheimer's disease (AD). This perspective shows a possible interrelation of these factors. AbetaPP, the precursor of Abeta which represents the main constituent of amyloid plaques, is involved in Cu homeostasis in mammals. In vitro observations and in vivo data obtained from AbetaPP mouse models provide strong evidence that AbetaPP and the resulting Abeta overproduction facilitate intracellular Cu to leave the cell. An increased Cu efflux seems to lead to Cu deficiency and, subsequently, reduced SOD-1 activity. The Cu-dependent SOD-1 activity is the main enzyme involved in detoxifying free radicals. Several reports have shown that oxidative stress is an invariable age-dependent feature in the brain of AD patients. Increased oxidative stress leads to an increase in intraneuronal Abeta accumulation, which has been shown to be the main trigger for neuronal loss in transgenic mouse models. Thus, we conclude that bioavailability of Cu is a crucial point for the pathogenesis of AD.

Alzheimer Disease↗