It is suggested that the fibrillar amyloid beta peptide (Aβ) in brain plays a direct role in neurodegeneration in Alzheimer's disease, probably through activation of reactive oxygen species formation. Free radicals and numerous neurotoxins elicit DNA damage that subsequently activates poly(ADP-ribose) polymerase (PARP, EC 2.4.2.30). In this study the effect of neurotoxic fragment (25-35) of full length Aβ peptide on PARP activity in adult and aged rat hippocampus was investigated. In adult (4 month old) rat hippocampus the Aβ 25-35 peptide significantly enhanced PARP activity by about 80% but had no effect on PARP activity in cerebral cortex and in hippocampus from aged (24-27 month old) rats. The effect of Aβ peptide was reduced by half by the nitric oxide synthase inhibitor N-nitro-L-arginine. Stimulation of glutamate receptor(s) itself enhanced PARP activity by about 80% in adult hippocampus. However, Aβ 25-35 did not exert any additional stimulatory effect. These results indicate that Aβ, through NO and probably other free radicals, induces activation of DNA bound PARP activity exclusively in adult but not in aged hippocampus.
The self-assembling tendency and protein complexation capability of dyes related to Congo red and also some dyes of different structure were compared to explain the mechanism of Congo red binding and the reason for its specific affinity for β-structure. Complexation with proteins was measured directly and expressed as the number of dye molecules bound to heat-aggregated IgG and to two light chains with different structural stability. Binding of dyes to rabbit antibodies was measured indirectly as the enhancement effect of the dye on immune complex formation. Self-assembling was tested using dynamic light scattering to measure the size of the supramolecular assemblies. In general the results show that the supramolecular form of a dye is the main factor determining its complexation capability. Dyes that in their compact supramolecular organization are ribbon-shaped may adhere to polypeptides of β-conformation due to the architectural compatibility in this unique structural form. The optimal fit in complexation seems to depend on two contradictory factors involving, on the one hand, the compactness of the non-covalently stabilized supramolecular ligand, and the dynamic character producing its plasticity on the other. As a result, the highest protein binding capability is shown by dyes with a moderate self-assembling tendency, while those arranging into either very rigid or very unstable supramolecular entities are less able to bind.
In 3D domain swapping, first described by Eisenberg, a structural element of a monomeric protein is replaced by the same element from another subunit. This process requires partial unfolding of the closed monomers that is then followed by adhesion and reconstruction of the original fold but from elements contributed by different subunits. If the interactions are reciprocal, a closed-ended dimer will be formed, but the same phenomenon has been suggested as a mechanism for the formation of open-ended polymers as well, such as those believed to exist in amyloid fibrils. There has been a rapid progress in the study of 3D domain swapping. Oligomers higher than dimers have been found, the monomer-dimer equilibrium could be controlled by mutations in the hinge element of the chain, a single protein has been shown to form more than one domain-swapped structure, and recently, the possibility of simultaneous exchange of two structural domains by a single molecule has been demonstrated. This last discovery has an important bearing on the possibility that 3D domain swapping might be indeed an amyloidogenic mechanism. Along the same lines is the discovery that a protein of proven amyloidogenic properties, human cystatin C, is capable of 3D domain swapping that leads to oligomerization. The structure of do-main-swapped human cystatin C dimers explains why a naturally occurring mutant of this protein has a much higher propensity for aggregation, and also suggests how this same mechanism of 3D domain swapping could lead to an open-ended polymer that would be consistent with the cross-β structure, which is believed to be at the heart of the molecular architecture of amyloid fibrils.
Congophilic angiopathies (CAA) are a group of neurodegenerations caused by amyloid deposition in the vessel walls. Amyloids are molecularly different and, as in all amyloidoses, CAA may be hereditary caused by mutations in a precursor for a given amyloid or sporadic of unknown cause. “Amyloid” is a generic terms to define diverse proteins of common physicochemical properties. In particular, they are congophilic (stained with Congo red), they fluorescent following staining with thioflavin S and they are composed of fibrils which are visible under transmission electron microscope. In this review we will cover: • dementia of BRI family: – familial British dementia, FBD (peptide ABri), – familial Danish dementia, FDD (peptide ADan); • hereditary cerebral haemorrhage with amyloidosis, Dutch type, HCHWA-D (peptide Aβ); • hereditary cerebral haemorrhage with amyloidosis, Icelandic type, HCHWA-I (cystatin C); • CAA associated with Alzheimer disease (peptide Aβ); • familial Finnish amyloidosis (gelsolin).
PL
Kongofilne angiopatie (ang. congophilic angiopathy, CAA) stanowią grupę chorób neurozwyrodnieniowych charakteryzujących się odkładaniem w ścianach naczyń ośrodkowego układu nerwowego (OUN) amyloidu o różnym składzie molekularnym. Jak wszystkie amyloidozy, CAA występują zarówno jako formy dziedziczne, uwarunkowane mutacjami w genach kodujących prekursor amyloidu, jak i postaci sporadyczne. W niniejszym przeglądzie zostaną omówione: - otępienia typu BRI: - rodzinne otępienie brytyjskie (ang. familial British dementia, FBD), - rodzinne otępienie duńskie (ang. familial Danish dementia, FDD); - dziedziczny krwotok mózgowy z amyloidozą typu holenderskiego (ang. hereditary cerebral haemorrhage with amyloidosis, Dutch type, HCHWA-D); - dziedziczny krwotok mózgowy z amyloidozą typu islandzkiego (ang. hereditary cerebral haemorrhage with amyloidosis, Icelandic type, HCHWA-I); - CAA towarzysząca chorobie Alzheimera; - CAA spowodowana odkładaniem gelsoliny – amyloidoza rodzinna typu fińskiego. We wszystkich tych chorobach występuje odkładanie się wokół naczyń amyloidów. Amyloidy są heterogenną grupą białek posiadających wspólne właściwości fizykochemiczne: kongofilię (barwienie czerwienią Kongo), fluorescencje po zabarwieniu tioflawiną S oraz tworzenie włókien obserwowanych w mikroskopie elektronowym. Amyloidy powstają z białek prekursorowych w wyniku ograniczonej proteolizy i zmiany konformacji z a-helikalnej na b-kartkę.
currently available pharmacotherapeutics (cholinesterase inhibitors and memantin) for Alzheimer’s disease (AD) exert mainly symptomatic effect and doubtful, if any, disease-modifying activities. Strategies of active and passive immunization were very successful in the last 10 years, mainly, however, with the use of experimental animal models of the disease. More recently, several human trials have been undertaken with mixed results obtained. Some support was found for the idea that immunotherapy may influence natural disease history, at least at the level of neuropathology and biomarkers and, to the less extend, neuroimaging findings and cognition. The paper presents recent developments in the use of immunotherapy of AD both with animal pasywmodels as well as human clinical trials. An attempt is also made to elucidate possible mechanisms of action of this novel treatment approach. Particularly, the difficulties in translating results obtained in animal studies into clinical trials in humans has been underlined and discussed. The results of the very first human trial with the use of AN-1792 vaccination are critically discussed with special reference to the possible mechanisms of the observed severe complications of this treatment modality (brain inflammation). currently, several other studies with active immunization are on the way, in which novel technologies diminishing the risk of brain inflammation were used. Finally, article presents several clinical trials with the use of passive immunization strategies, showing the advantages of this approach, particularly in the context of tolerability.
PL
Obecnie dostępne metody leczenia choroby Alzheimera (inhibitory cholinesterazy i memantyna) mają prawdopodobnie głównie działanie objawowe, a ich wpływ na naturalny przebieg choroby jest wątpliwy. Strategie aktywnej i pasywnej immunizacji są intensywnie badane przez ostatnie 10 lat. Wyniki badań eksperymentalnych oraz wstępne wyniki badań chorych z AD wskazują, że działanie immunoterapii może wykraczać poza efekt objawowy i wpływać nie tylko na objawy (poznawcze, behawioralne), ale także na progresję neuropatologiczną i, prawdopodobnie, biomarkery. W pracy przedstawiono wyniki badań z wykorzystaniem modeli zwierzęcych AD i użyciem metod aktywnej i pasywnej immunizacji anty-Ab. Omówiono trudności z przełożeniem wyników uzyskanych z wykorzystaniem zwierząt laboratoryjnych na potencjalne metody terapeutyczne u ludzi. Opisano ponadto pierwsze wyniki badań na ludziach i podjęto próbę odpowiedzi na pytanie o mechanizmy działania immunoterapii w AD. Krytycznej analizie poddano wyniki pierwszych badań klinicznych na ludziach z użyciem szczepionki AN-1792, ze szczególnym uwzględnieniem możliwych przyczyn obserwowanych w tych badaniach powikłań (zapalenie mózgu). Obecnie prowadzonych jest kilka innych badań z aktywną immunizacją, w których zastosowano technologie zmniejszające ryzyko zapalenia mózgu. W pracy omówiono także prowadzone obecnie próby kliniczne z wykorzystaniem technik pasywnej immunizacji i wskazano na potencjalne przewagi tej metody nad immunizacją aktywną, zwłaszcza w kontekście tolerancji leczenia.
There is a natural protein form, insoluble and resistant to proteolysis, adopted by many proteins independently of their amino acid sequences via specific misfolding-aggregation process. This dynamic process occurs in parallel with or as an alternative to physiologic folding, generating toxic protein aggregates that are deposited and accumulated in various organs and tissues. These proteinaceous deposits typically represent bundles of β-sheet-enriched fibrillar species known as the amyloid fibrils that are responsible for serious pathological conditions, including but not limited to neurodegenerative diseases, grouped under the term amyloidoses. The proteins that might adopt this fibrillar conformation are some globular proteins and natively unfolded (or intrinsically disordered) proteins. Our work shows that intrinsically disordered and intrinsically ordered proteins can be reliably identified, discriminated, and differentiated by analyzing their polarity profiles generated using a computational tool known as the polarity index method (Polanco & Samaniego, 2009; Polanco et al., 2012; 2013; 2013a; 2014; 2014a; 2014b; 2014c; 2014d). We also show that proteins expressed in neurons can be differentiated from proteins in these two groups based on their polarity profiles, and also that this computational tool can be used to identify proteins associated with amyloidoses. The efficiency of the proposed method is high (i.e. 70%) as evidenced by the analysis of peptides and proteins in the APD2 database (2012), AVPpred database (2013), and CPPsite database (2013), the set of selective antibacterial peptides from del Rio et al. (2001), the sets of natively unfolded and natively folded proteins from Oldfield et al. (2005), the set of human revised proteins expressed in neurons, and non-human revised proteins expressed in neurons, from the Uniprot database (2014), and also the set of amyloidogenic proteins from the AmyPDB database (2014).
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