Browsing by Author "Cardoso, Isabel"
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- Bridging cyanobacteria to neurodegenerative diseases: a new potential source of bioactive compounds against Alzheimer’s diseasePublication . Castaneda, Andrea; Ferraz, Ricardo; Vieira, Mónica; Cardoso, Isabel; Vasconcelos, Vítor; Martins, RosárioNeurodegenerative diseases (NDs) represent a drawback in society given the ageing population. Dementias are the most prevalent NDs, with Alzheimer’s disease (AD) representing around 70% of all cases. The current pharmaceuticals for AD are symptomatic and with no effects on the progression of the disease. Thus, research on molecules with therapeutic relevance has become a major focus for the scientific community. Cyanobacteria are a group of photosynthetic prokaryotes rich in biomolecules with confirmed activity in pathologies such as cancer, and with feasible potential in NDs such as AD. In this review, we aimed to compile the research works focused in the anti-AD potential of cyanobacteria, namely regarding the inhibition of the enzyme β-secretase (BACE1) as a fundamental enzyme in the generation of β-amyloid (Aβ), the inhibition of the enzyme acetylcholinesterase (AChE) lead to an increase in the availability of the neurotransmitter acetylcholine in the synaptic cleft and the antioxidant and anti-inflammatory effects, as phenomena associated with neurodegeneration mechanisms.
- Effects of transthyretin stabilization by wine polyphenols in the modulation of Alzheimer’s diseasePublication . Rodrigues, Daniela; Santos, Luís M.; Alemi, Mobina; Ribeiro, Carlos; Saraiva, Maria João; Mateus, Nuno; Cardoso, IsabelAlzheimer’s disease (AD) is the most common type of dementia, accounting for 60% to 80% of all cases worldwide. Senile plaques, one of AD hallmarks, are mainly constituted of A peptide. Transthyretin (TTR) has been described to exert a neuroprotective effect in AD by interacting with A. This activity is dependent on its stability, thus compounds that stabilize TTR tetrameric fold increase TTR/A binding. Most of the compounds identified as TTR stabilizers belong to the group of non-steroid anti inflammatory drugs and compete with thyroxine (T4), the natural TTR stabilizer. Investigate the neuroprotective potential of wine polyphenols (Resveratrol, Catechin, Malvidin and Polyphenolic Extract) by exploring their ability to improve TTR/A interaction.
- S100A6 Amyloid Fibril Formation Is Calcium-modulated and Enhances Superoxide Dismutase-1 (SOD1) AggregationPublication . Botelho, Hugo; S. Leal, Sónia; Cardoso, Isabel; Yanamandra, Kiran; Morozova-Roche, Ludmilla A.; Fritz, Günter; Gomes, Cláudio M.S100A6 is a small EF-hand calcium- and zinc-binding protein involved in the regulation of cell proliferation and cytoskeletal dynamics. It is overexpressed in neurodegenerative disorders and a proposed marker for Amyotrophic Lateral Sclerosis (ALS). Following recent reports of amyloid formation by S100 proteins, we investigated the aggregation properties of S100A6. Computational analysis using aggregation predictors Waltz and Zyggregator revealed increased propensity within S100A6 helices HI and HIV. Subsequent analysis of Thioflavin-T binding kinetics under acidic conditions elicited a very fast process with no lag phase and extensive formation of aggregates and stacked fibrils as observed by electron microscopy. Ca2+ exerted an inhibitory effect on the aggregation kinetics, which could be reverted upon chelation. An FT-IR investigation of the early conformational changes occurring under these conditions showed that Ca2+ promotes anti-parallel β-sheet conformations that repress fibrillation. At pH 7, Ca2+ rendered the fibril formation kinetics slower: time-resolved imaging showed that fibril formation is highly suppressed, with aggregates forming instead. In the absence of metals an extensive network of fibrils is formed. S100A6 oligomers, but not fibrils, were found to be cytotoxic, decreasing cell viability by up to 40%. This effect was not observed when the aggregates were formed in the presence of Ca2+. Interestingly, native S1006 seeds SOD1 aggregation, shortening its nucleation process. This suggests a cross-talk between these two proteins involved in ALS. Overall, these results put forward novel roles for S100 proteins, whose metal-modulated aggregation propensity may be a key aspect in their physiology and function.
- Stability of the transthyretin molecule as a key factor in the interaction with a-beta peptide--relevance in Alzheimer's diseasePublication . Ribeiro, Carlos A.; Saraiva, Maria João; Cardoso, IsabelTransthyretin (TTR) protects against A-Beta toxicity by binding the peptide thus inhibiting its aggregation. Previous work showed different TTR mutations interact differently with A-Beta, with increasing affinities correlating with decreasing amyloidogenecity of the TTR mutant; this did not impact on the levels of inhibition of A-Beta aggregation, as assessed by transmission electron microscopy. Our work aimed at probing differences in binding to A-Beta by WT, T119M and L55P TTR using quantitative assays, and at identifying factors affecting this interaction. We addressed the impact of such factors in TTR ability to degrade A-Beta. Using a dot blot approach with the anti-oligomeric antibody A11, we showed that A-Beta formed oligomers transiently, indicating aggregation and fibril formation, whereas in the presence of WT and T119M TTR the oligomers persisted longer, indicative that these variants avoided further aggregation into fibrils. In contrast, L55PTTR was not able to inhibit oligomerization or to prevent evolution to aggregates and fibrils. Furthermore, apoptosis assessment showed WT and T119M TTR were able to protect against A-Beta toxicity. Because the amyloidogenic potential of TTR is inversely correlated with its stability, the use of drugs able to stabilize TTR tetrameric fold could result in increased TTR/ABeta binding. Here we showed that iododiflunisal, 3-dinitrophenol, resveratrol, [2-(3,5-dichlorophenyl)amino] (DCPA) and [4- (3,5-difluorophenyl)] (DFPB) were able to increase TTR binding to A-Beta; however only DCPA and DFPB improved TTR proteolytic activity. Thyroxine, a TTR ligand, did not influence TTR/A-Beta interaction and A-Beta degradation by TTR, whereas RBP, another TTR ligand, not only obstructed the interaction but also inhibited TTR proteolytic activity. Our results showed differences between WT and T119M TTR, and L55PTTR mutant regarding their interaction with A-Beta and prompt the stability of TTR as a key factor in this interaction, which may be relevant in AD pathogenesis and for the design of therapeutic TTR-based therapies.
- Testing the therapeutic potential of doxycycline in a drosophila melanogaster model of Alzheimer diseasePublication . Costa, Rita; Speretta, Elena; Crowther, Damian C.; Cardoso, IsabelTherapies for Alzheimer disease that reduce the production of pathogenic amyloid beta (A beta) peptides have been associated with a range of unwanted effects. For this reason, alternative strategies that promote the clearance of the peptide by preventing its aggregation and deposition in the brain have been favored. In this context we have studied doxycycline, a member of the tetracycline family of antibiotics that has shown neuroprotective effects in a number of models of neurodegenerative disease. We investigated the neuroprotective potential of doxycycline in a Drosophila model of A beta toxicity and sought to correlate any effects with the aggregation state of the peptide. We found that administration of doxycycline to A beta 42-expressing flies did not improve their lifespan but was able to slow the progression of their locomotor deficits. We also measured the rough eye phenotype of transgenic flies expressing the E22G variant of A beta 42 and showed that doxycycline administration partially rescued the toxicity of A beta in the developing eye. We correlated these in vivo effects with in vitro observations using transmission electron microscopy, dynamic light scattering, and thioflavin T binding. We found that doxycycline prevents A beta fibrillization and favors the generation of smaller, non-amyloid structures that were nontoxic as determined by the lack of caspase 3 activation in a neuroblastoma cell line. Our confirmation that doxycycline can prevent amyloid beta toxicity both in vitro and in vivo supports its therapeutic potential in AD.