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![Loss of antiparallel β-sheets for the (A) aggregation pathway (Aβ o ) and (B) disaggregation of (Aβ f ) following CD during 1 and 5 days. All experiments were conducted using a Aβ:dendrimers ratio of 1:1, [Aβ] = 25 μM, and under constant agitation at 37 °C. Error bars = SD; n = 3. CD data were fitted using BeStSelRMSD: 1.0283; NRMSD: 0.04966.](profile/Vicente-Dominguez-Arca/publication/356874958/figure/fig3/AS:1106393373388801@1640796144641/Loss-of-antiparallel-b-sheets-for-the-A-aggregation-pathway-Ab-o-and-B.png)
Loss of antiparallel β-sheets for the (A) aggregation pathway (Aβ o ) and (B) disaggregation of (Aβ f ) following CD during 1 and 5 days. All experiments were conducted using a Aβ:dendrimers ratio of 1:1, [Aβ] = 25 μM, and under constant agitation at 37 °C. Error bars = SD; n = 3. CD data were fitted using BeStSelRMSD: 1.0283; NRMSD: 0.04966.
Source publication
The self-assembly of amyloid-β (Aβ) generates cytotoxic oligomers linked to the onset and progression of Alzheimer's disease (AD). As many fundamental molecular pathways that control Aβ aggregation are yet to be unraveled, an important strategy to control Aβ cytotoxicity is the development of bioactive synthetic nanotools capable of interacting wit...
Contexts in source publication
Context 1
... showed that all dendrimers perturbed the Aβ secondary structure ( Figures S35−S42), probably leading to the formation of noncytotoxic oligomers. CD spectra were fitted using the BeStSel method 26 for secondary structure estimation ( Figure 4). After 1 day of incubation, a decrease in the antiparallel β-sheets for all Aβ o :dendrimer ratios was already visible, which were further reduced over 5 days of incubation. ...
Context 2
... we evaluated the morphological changes of the Aβ f aggregates upon contact with the dendrimers by AFM ( Figure 5) and STEM ( Figure S44). As expected, a reduction in the number of small aggregates is observed, a morphological presentation compatible with cytotoxic oligomers or other small Aβ species. ...
Context 3
... addition, elongated fibrils are replaced by unstructured aggregates (condensed and less organized) and/ or shorter fibers as a result of the interaction between Aβ f and the dendrimers. When the interaction was studied on a per Ga unit basis by AFM, the dendrimers with higher number of Ga units revealed to be more effective than monovalent Ga to disrupt the Aβ f assemblies ( Figure S45). Overall, the dendrimers were able to remodel the Aβ aggregation state into species with a morphology compatible with a reduced cytotoxicity. ...
Context 4
... blot (WB, using the 6E10 antibody) allowed the quantification of the aggregates of different sizes, i.e., monomers, oligomers, and fibrils, produced during the assembly (Aβ o ) and disassembly (Aβ f ) processes ( Figure 6). In both cases, 2G1-GaOH shows the highest reduction in the oligomeric and monomeric species after 1 and 5 days of incubation ( Figures S46 and S47). The antibody 6E10 is specific for the 1−16 amino acids of the Aβ sequence, requiring an intact N-terminal epitope that encloses the amino acid sequence 3−8: Glu−Phe−Arg−His−Asp−Ser. From the MD simulations, we found that dendrimers exhibit strong and stable H-bonding interactions with Glu residues, so these results are compatible with the ability of 2G1-GaOH to interact directly with the Aβ N-terminal, blocking the epitope recognized by the 6E10 antibody. ...
Citations
... Polyphenols like gallic acid (GA) and its derivatives are studied for metal chelation, antioxidant, anti-inflammatory, Aβ 42 aggregation inhibition, and neuroprotective properties [26][27][28]. Additionally, CDPs are a promising category of biologically active compounds, highly regarded for their antioxidant, anti-inflammatory, and neuroprotective properties [29]. ...
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the build-up of extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Ferroptosis, an iron (Fe)-dependent form of cell death plays a significant role in the multifaceted AD pathogenesis through generation of reactive oxygen species (ROS), mitochondrial damage, lipid peroxidation, and reduction in glutathione peroxidase 4 (GPX4) enzyme activity and levels. Aberrant liquid-liquid phase separation (LLPS) of tau drives the growth and maturation of NFTs contributing to AD pathogenesis. In this study, we strategically combined the structural and functional properties of gallic acid (GA) and cyclic dipeptides (CDPs) to synthesize hybrid molecules that effectively target both ferroptosis and amyloid toxicity in AD. This innovative approach marks a paradigm shift from conventional therapeutic strategies. This is the first report of a synthetic small molecule (GCTR) that effectively combats ferroptosis, simultaneously restoring enzymatic activity and enhancing cellular levels of its master regulator, GPX4. Further, GCTR disrupts Fe³⁺-induced LLPS of tau, and aids in attenuation of abnormal tau fibrillization. The synergistic action of GCTR in combating both ferroptosis and amyloid toxicity, bolstered by GPX4 enhancement and modulation of Fe³⁺-induced tau LLPS, holds promise for the development of small molecule-based novel therapeutics for AD.
... Since then, this property has been explored in different dendritic architectures and demonstrated in several fibrillar proteins. These properties were further described in PAMAM [19,[104][105][106][107], PPI [22,108], cationic phosphorous dendrimers (CPD) [21,24,109], GATG dendrimers functionalised with morpholine groups [110] or gallic acid [111], carbosilane dendrimers [112,113], viologen-phosphorus dendrimers (VPD) [114][115][116][117], and different types of glycodendrimers [20,26,108,[118][119][120][121][122][123]. Most of these dendritic macromolecules have demonstrated the ability to inhibit fibrillation, degrade pre-existent aggregates, and protect cells from the toxic effects of the aggregation species for amyloid species of Aβ, PrP, α-synuclein, and others. ...
... If breakage is faster than the elongation, fibrils are converted to monomeric structures, hampering fibrillation. This hypothesis is validated by the ability of dendrimers to degrade pre-existent aggregates, which has been reported in several dendritic architectures [19,21,106,109,111,[127][128][129]. The dendrimer/peptide ratio also influences the secondary structure and morphology of fibrils. ...
... On the other hand, electrostatic interaction solely cannot explain the anti-amyloidogenic properties of the dendrimers as neutral dendrimers have shown a similar ability to inhibit amyloid aggregation and degrade previously formed aggregates [20,108,111,118,119,121]. Several studies of maltose-functionalised PPI glycodendrimers (mPPI) have shown that these dendrimers can reduce the dendrimer cytotoxicity while maintaining the same anti-amyloidogenic properties of cationic PPI dendrimers. ...
Alzheimer’s disease (AD) is the most prevalent form of dementia. It affects more than 30 million people worldwide and costs over US$ 1.3 trillion annually. AD is characterized by the brain accumulation of amyloid β peptide in fibrillar structures and the accumulation of hyperphosphorylated tau aggregates in neurons, both leading to toxicity and neuronal death. At present, there are only seven drugs approved for the treatment of AD, of which only two can slow down cognitive decline. Moreover, their use is only recommended for the early stages of AD, meaning that the major portion of AD patients still have no disease-modifying treatment options. Therefore, there is an urgent need to develop efficient therapies for AD. In this context, nanobiomaterials, and dendrimers in particular, offer the possibility of developing multifunctional and multitargeted therapies. Due to their intrinsic characteristics, dendrimers are first-in-class macromolecules for drug delivery. They have a globular, well-defined, and hyperbranched structure, controllable nanosize and multivalency, which allows them to act as efficient and versatile nanocarriers of different therapeutic molecules. In addition, different types of dendrimers display antioxidant, anti-inflammatory, anti-bacterial, anti-viral, anti-prion, and most importantly for the AD field, anti-amyloidogenic properties. Therefore, dendrimers can not only be excellent nanocarriers, but also be used as drugs per se. Here, the outstanding properties of dendrimers and derivatives that make them excellent AD nanotherapeutics are reviewed and critically discussed. The biological properties of several dendritic structures (dendrimers, derivatives, and dendrimer-like polymers) that enable them to be used as drugs for AD treatment will be pointed out and the chemical and structural characteristics behind those properties will be analysed. The reported use of these nanomaterials as nanocarriers in AD preclinical research is also presented. Finally, future perspectives and challenges that need to be overcome to make their use in the clinic a reality are discussed.
... It is appropriate to mention here some other interesting approaches using modified bio-conjugated PAMAM in the context of therapeutic efforts against AD. Small dendrimers with terminal units derived from trehalose or gallic acid ( Figure 15) have been studied for their potential as inhibitors of protein aggregation [88,89]. Trehalose, a disaccharide, and gallic acid, a natural polyphenol, both interfere with Aβ nucleation and aggregation processes. ...
Nanomaterials play an increasingly important role in current medicinal practice. As one of the most significant causes of human mortality, and one that is increasing year by year, Alzheimer’s disease (AD) has been the subject of a very great body of research and is an area in which nanomedicinal approaches show great promise. Dendrimers are a class of multivalent nanomaterials which can accommodate a wide range of modifications that enable them to be used as drug delivery systems. By means of suitable design, they can incorporate multiple functionalities to enable transport across the blood–brain barrier and subsequently target the diseased areas of the brain. In addition, a number of dendrimers by themselves often display therapeutic potential for AD. In this review, the various hypotheses relating to the development of AD and the proposed therapeutic interventions involving dendrimer–base systems are outlined. Special attention is focused on more recent results and on the importance of aspects such as oxidative stress, neuroinflammation and mitochondrial dysfunction in approaches to the design of new treatments.
... GATG dendrimers are composed of a gallic acid core, responsible for the multivalency, and long triethylene glycol spacer arms that give flexibility to the dendritic structure. They have been exploited for the preparation of drug [29,30] and gene delivery [31] systems, and the construction of monodisperse nanotools to modulate the complex mechanisms governing multivalent interactions [32][33][34][35]. 2[G4]-N 3 , which is prepared divergently from a triethylene glycol diamine core and the GATG repeating unit ( Figure 1A), carries 162 terminal azides that we have used for the bioconjugation of the AT11 aptamer by means of the strain-promoted azide-alkyne cycloaddition (SPAAC) [22][23][24]. ...
Herein, we describe the synthesis of an aptadendrimer by covalent bioconjugation of a gallic acid–triethylene glycol (GATG) dendrimer with the G-quadruplex (G4) AT11 aptamer (a modified version of AS1411) at the surface. We evaluated the loading and interaction of an acridine orange ligand, termed C8, that acts as an anticancer drug and binder/stabilizer of the G4 structure of AT11. Dynamic light scattering experiments demonstrated that the aptadendrimer was approximately 3.1 nm in diameter. Both steady-state and time-resolved fluorescence anisotropy evidenced the interaction between the aptadendrimer and C8. Additionally, we demonstrated that the iodine atom of the C8 ligand acts as an effective intramolecular quencher in solution, while upon complexation with the aptadendrimer, it adopts a more extended conformation. Docking studies support this conclusion. Release experiments show a delivery of C8 after 4 h. The aptadendrimers tend to localize in the cytoplasm of various cell lines studied as demonstrated by confocal microscopy. The internalization of the aptadendrimers is not nucleolin-mediated or by passive diffusion, but via endocytosis. MTT studies with prostate cancer cells and non-malignant cells evidenced high cytotoxicity mainly due to the C8 ligand. The rapid internalization of the aptadendrimers and the fluorescence properties make them attractive for the development of potential nanocarriers.
Early detection and treatment are crucial for Alzheimer's disease (AD) management. Current diagnostic and therapeutic methods focus on late‐stage amyloid fibrils and plaques, overlooking toxic soluble amyloid β oligomers (AβOs) accumulating early in AD. A multifunctional liposome‐based platform is designed for early diagnosis and therapy of AD, leveraging a novel self‐assembled cyclic d , l ‐α‐peptide ( CP‐2 ) that selectively targets AβOs. Biocompatible CP‐2 conjugated liposomes (CP‐2‐LPs) effectively disrupt Aβ aggregation and mitigate Aβ‐mediated toxicity in human neuroblastoma cells. In transgenic Caenorhabditis elegans AD models, CP‐2‐LPs significantly outperformed free CP‐2 by improving cognitive and behavioral functions, extending lifespan, and reducing toxic AβO levels. Intravenous injection of fluorescently labeled CP‐2‐LPs reveals effective blood‐brain barrier penetration, with significantly higher brain fluorescence in transgenic mice than WT, enabling precise diagnosis. These findings underscore CP‐2‐LPs as a valuable tool for early detection and targeted therapy in AD.
The potential for dendrimers, highly branching three-dimensional macromolecules, to function as drug delivery vehicles has been extensively investigated. They have special qualities such as a well-defined structure, a large surface area, and the capacity to capture and release many kinds of chemicals, including naturally derived compounds.
Phytoconstituents (PCs) are naturally occurring chemical substances that are present in plants and have a range of medicinal benefits. However, problems including poor solubility, low adsorption, and instability frequently constrained their practical utilization. Dendrimers are capable of binding PC molecules either on their surface or within their internal cavities and assist their regulated and targeted delivery in vivo, mainly by advancing their solubility and stability or enabling their controlled release, targeting, and combinational therapy. Thus, as a whole, dendrimers provide promising approaches for the effective delivery of PCs, eliminating their shortcomings and enhancing their therapeutic potential.
Still, dendrimer-based delivery systems are a topic of current study and further research is required to understand the physicochemical and biological properties of dendrimers, their interaction with PCs, and strategies of dendrimer-PC formulation development, which may improve the designing, effectiveness, and safety aspects of dendrimer-based PC delivery systems.
The abnormal amyloid‐β accumulation is essential and obbligato in Alzheimer's disease pathogenesis and natural polyphenols exhibited great potential as amyloid aggregation inhibitors. However, the poor metabolic stability, low bioavailability, and weak blood‐brain barrier crossing ability of natural polyphenol molecules fail to meet clinical needs. Here, we develop a universal protocol to prepare natural polyphenolic nanodots by heating in aqueous solution without unacceptable additives. The nanodots are able to not only inhibit amyloid‐β fibrillization and trigger the fibrils disaggregation, but mitigate the amyloid‐β plaques induced cascade impairments including normalizing oxidative microenvironment, altering microglial polarization, and rescuing neuronal death and synaptic loss, which resulting in significant improvements in recognition and cognition deficits in transgenic mice. More importantly, natural polyphenolic nanodots possess stronger anti‐amyloidogenic performance compared with small molecule, as well as penetrate the blood‐brain barrier. The excellent biocompatibility further guarantees the potential of natural polyphenolic nanodots for clinical applications. It is expected that natural polyphenolic nanodots provides an attractive paradigm to support the development of the therapeutics for Alzheimer's disease.
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Alzheimer's disease (AD) is a common neurodegenerative disease, which seriously impairs human health and life. At present, scientists have proposed more than a dozen hypotheses about the pathogenesis of AD, including the tau propagation hypothesis. However, the exact ultimate pathogenic factor of AD remains unknown. Based on the current hypotheses, some anti-AD drugs (e.g., donepezil and Ketamine) have been developed and used in clinical treatment, which fall into two main categories, acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonists, the former representative drug is donepezil, and the latter representative drug is memantine. Since these drugs have undesirable side effects, it is necessary to find safer alternatives for AD treatment. Interestingly, dietary phytochemicals have the advantages of wide source, safety, and high biological activity, which is the natural route for screening anti-AD drugs. In this study, several representatives’ dietary phytochemicals with anti-AD effect, including resveratrol, lycopene, gallic acid, berberine, ginsenoside Rg1, pseudoginsenoside-F11, ginsenoside Rh2, artemisinin, and torularhodin were selected from the published data over the last 10 years and their potential molecular mechanisms and clinical applications reviewed in the treatment of AD.
Significance:
Reactive oxygen species (ROS) are crucial signaling molecules in the regulation of numerous physiological activities including the formation and function of the central nervous system (CNS). So far, many functional antioxidant nanomedicines with ROS scavenging capability to reduce oxidative stress in AD have been developed for both imaging and therapy of AD.
Recent advances:
This review focuses on the most recent advances in antioxidant nanomedicines such as ROS-scavenging nanoparticles, nanoparticles with intrinsic antioxidant activity, and drug-loaded anti-oxidant nanoparticles for AD theranostics. In addition to antioxidant nanomedicines, the emerging phototherapy treatment paradigms and the promising preclinic drug carriers, such as exosomes and liposomes, are also introduced.
Critical issues:
Generally, excessive generation of ROS can cause lipid peroxidation, oxidative DNA as well as protein damage, aggravating pathogenic alterations, accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles in the brain. These negative factors further cause cell death, which is the beginning of Alzheimer's disease (AD).
Future directions:
We anticipate that this review will help researchers in the area of preclinical research and clinical translation of antioxidant nanomedicines for AD imaging and therapy.
