Search Results (29)

Soluble oligomeric forms of Amyloid-β (Aβ) are considered the major toxic species leading to the neurodegeneration underlying Alzheimer’s disease (AD). Therefore, drugs that prevent oligomer formation might be promising. The atypical dipeptide GAL-201 is orally bioavailable and interferes as a modulator of Aβ aggregation. It binds to aggregation-prone, misfolded Aβ monomers with high selectivity and affinity, thereby preventing the formation of toxic oligomers. Here, we demonstrate that the previously observed protective effect of GAL-201 on synaptic plasticity occurs irrespective of shortages and post-translational modifications (tested isoforms: Aβ_1–42, Aβ(p3-42), Aβ_1–40 and 3NTyr(10)-Aβ). Interestingly, the neuroprotective activity of a single dose of GAL-201 was still present after one week and correlated with a prevention of Aβ-induced spine loss. Furthermore, we could observe beneficial effects on spine morphology as well as the significantly reduced activation of proinflammatory microglia and astrocytes in the presence of an Aβ_1–42-derived toxicity. In line with these in vitro data, GAL-201 additionally improved hippocampus-dependent spatial learning in the “tgArcSwe” AD mouse model after a single subcutaneous administration. By this means, we observed changes in the deposition pattern: through the clustering of misfolded monomers as off-pathway non-toxic Aβ agglomerates, toxic oligomers are removed. Our results are in line with previously collected preclinical data and warrant the initiation of Investigational New Drug (IND)-enabling studies for GAL-201. By demonstrating the highly efficient detoxification of β-sheet monomers, leading to the neutralization of Aβ oligomer toxicity, GAL-201 represents a promising drug candidate against Aβ-derived pathophysiology present in AD. Full article

Amyloid-β1–42 (Aβ42) forms highly stable and insoluble fibrillar structures, representing the principal components of the amyloid plaques present in the brain of Alzheimer’s disease (AD) patients. The involvement of Aβ42 in AD-associated neurodegeneration has also been demonstrated, in particular for smaller and soluble aggregates (oligomers). Based on these findings and on genetic evidence, Aβ42 aggregates are considered key players in the pathogenesis of AD and targets for novel therapies. Different approaches are currently used to detect the various aggregation states of Aβ peptide, including spectrophotometric methods, imaging techniques, and immunoassays, but all of these have specific limitations. To overcome them, we have recently exploited the peculiar properties of surface plasmon resonance (SPR) to develop an immunoassay capable of selectively detecting monomers and oligomers, discriminating them also from bigger fibrils in a mixture of different aggregated species, without any manipulation of the solution. In the present study, we extended these previous studies, showing that the SPR-based immunoassay makes it possible to unveil the fibril fragmentation induced mechanically, a result difficult to be conveniently and reliably assessed with other approaches. Moreover, we show that SPR-recognized fibril fragments are more toxic than the larger fibrillar structures, suggesting the relevance of the proposed SPR-based immunoassay. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid beta (Aβ) plaques in the brain. Aβ_1–42 is the main component of Aβ plaque, which is toxic to neuronal cells. Si nanowires (Si NWs) have the advantages of small particle size, high specific surface area, and good biocompatibility, and have potential application prospects in suppressing Aβ aggregation. In this study, we employed the vapor–liquid–solid (VLS) growth mechanism to grow Si NWs using Au nanoparticles as catalysts in a plasma-enhanced chemical vapor deposition (PECVD) system. Subsequently, these Si NWs were transferred to a phosphoric acid buffer solution (PBS). We found that Si NWs significantly reduced cell death in PC12 cells (rat adrenal pheochromocytoma cells) induced by Aβ_1–42 oligomers via double staining with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and fluorescein diacetate/propyl iodide (FDA/PI). Most importantly, pre-incubated Si NWs largely prevented Aβ_1–42 oligomer-induced PC12 cell death, suggesting that Si NWs exerts an anti-Aβ neuroprotective effect by inhibiting Aβ aggregation. The analysis of Fourier Transform Infrared (FTIR) results demonstrates that Si NWs reduce the toxicity of fibrils and oligomers by intervening in the formation of β-sheet structures, thereby protecting the viability of nerve cells. Our findings suggest that Si NWs may be a potential therapeutic agent for AD by protecting neuronal cells from the toxicity of Aβ_1–42. Full article

Alzheimer’s disease (AD) is characterized by the formation of senile plaques consisting of fibrillated amyloid-β (Aβ), dystrophic neurites, and the neurofibrillary tangles of tau. The oligomers/fibrillar Aβ damages the neurons or initiates an intracellular signaling cascade for neuronal cell death leading to Aβ toxicity. The Aβ is a 4 kDa molecular weight peptide originating from the C-terminal region of the amyloid precursor protein via proteolytic cleavage. Apart from the typical AD hallmarks, certain deficits in metabolic alterations have been identified. This study describes the emerging features of AD from the aspect of metabolic reprogramming in the main pathway of carbohydrate metabolism in the human brain. Particularly, the neurons in patients with AD favor glycolysis despite a normal mitochondrial function indicating a Warburg-like effect. In addition, certain dietary patterns are well known for their properties in preventing AD. Among those, a ketogenic diet may substantially improve the symptoms of AD. An effective therapeutic method for the treatment, mitigation, and prevention of AD has not yet been established. Therefore, the researchers pursue the development and establishment of novel therapies effective in suppressing AD symptoms and the elucidation of their underlying protective mechanisms against neurodegeneration aiming for AD therapy in the near future. Full article

The aggregation of amyloid-$\beta$ (A$\beta$) peptides, particularly of A${\beta }_{1-42}$, has been linked to the pathogenesis of Alzheimer’s disease. In this study, we focus on the conformational change of A${\beta }_{1-42}$ in the presence of glycosaminoglycans (GAGs) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids using molecular dynamics simulations. We analyze the conformational changes that occur in A$\beta$ by extracting the key structural features that are then used to generate transition networks. Using the same three features per network highlights the transitions from intrinsically disordered states ubiquitous in A${\beta }_{1-42}$ in solution to more compact states arising from stable $\beta$-hairpin formation when A${\beta }_{1-42}$ is in the vicinity of a GAG molecule, and even more compact states characterized by a $\alpha$-helix or $\beta$-sheet structures when A${\beta }_{1-42}$ interacts with a POPC lipid cluster. We show that the molecular mechanisms underlying these transitions from disorder to order are different for the A${\beta }_{1-42}$/GAG and A${\beta }_{1-42}$/POPC systems. While in the latter the hydrophobicity provided by the lipid tails facilitates the folding of A${\beta }_{1-42}$, in the case of GAG there are hardly any intermolecular A${\beta }_{1-42}$–GAG interactions. Instead, GAG removes sodium ions from the peptide, allowing stronger electrostatic interactions within the peptide that stabilize a $\beta$-hairpin. Our results contribute to the growing knowledge of the role of GAGs and lipids in the conformational preferences of the A$\beta$ peptide, which in turn influences its aggregation into toxic oligomers and amyloid fibrils. Full article

Recent studies have revealed that soluble amyloid-β oligomers (AβOs) play a pathogenetic role in Alzheimer’s disease (AD). Indeed, AβOs induce neurotoxic and synaptotoxic effects and are also critically involved in neuroinflammation. Oxidative stress appears to be a crucial event underlying these pathological effects of AβOs. From a therapeutic standpoint, new drugs for AD designed to remove AβOs or inhibit the formation of AβOs are currently being developed. However, it is also worth considering strategies for preventing AβO toxicity itself. In particular, small molecules with AβO toxicity-reducing activity have potential as drug candidates. Among such small molecules, those that can enhance Nrf2 and/or PPARγ activity can effectively inhibit AβO toxicity. In this review, I summarize studies on the small molecules that counteract AβO toxicity and are capable of activating Nrf2 and/or PPARγ. I also discuss how these interrelated pathways are involved in the mechanisms by which these small molecules prevent AβO-induced neurotoxicity and neuroinflammation. I propose that AβO toxicity-reducing therapy, designated ATR-T, could be a beneficial, complementary strategy for the prevention and treatment of AD. Full article

In Alzheimer’s disease (AD), accumulation of amyloid β-protein (Aβ) is one of the major mechanisms causing neuronal cell damage. Disruption of cell membranes by Aβ has been hypothesized to be the important event associated with neurotoxicity in AD. Curcumin has been shown to reduce Aβ-induced toxicity; however, due to its low bioavailability, clinical trials showed no remarkable effect on cognitive function. As a result, GT863, a derivative of curcumin with higher bioavailability, was synthesized. The purpose of this study is to clarify the mechanism of the protective action of GT863 against the neurotoxicity of highly toxic Aβ oligomers (Aβo), which include high-molecular-weight (HMW) Aβo, mainly composed of protofibrils in human neuroblastoma SH-SY5Y cells, focusing on the cell membrane. The effect of GT863 (1 μM) on Aβo-induced membrane damage was assessed by phospholipid peroxidation of the membrane, membrane fluidity, membrane phase state, membrane potential, membrane resistance, and changes in intracellular Ca²⁺ ([Ca²⁺]i). GT863 inhibited the Aβo-induced increase in plasma-membrane phospholipid peroxidation, decreased membrane fluidity and resistance, and decreased excessive [Ca²⁺]i influx, showing cytoprotective effects. The effects of GT863 on cell membranes may contribute in part to its neuroprotective effects against Aβo-induced toxicity. GT863 may be developed as a prophylactic agent for AD by targeting inhibition of membrane disruption caused by Aβo exposure. Full article

Neurodegenerative diseases are the result of progressive dysfunction of the neuronal activity and subsequent neuronal death. Currently, the most prevalent neurodegenerative diseases are by far Alzheimer’s (AD) and Parkinson’s (PD) disease, affecting millions of people worldwide. Although amyloid plaques and neurofibrillary tangles are the neuropathological hallmarks for AD and Lewy bodies (LB) are the hallmark for PD, current evidence strongly suggests that oligomers seeding the neuropathological hallmarks are more toxic and disease-relevant in both pathologies. The presence of small soluble oligomers is the common bond between AD and PD: amyloid β oligomers (AβOs) and Tau oligomers (TauOs) in AD and α-synuclein oligomers (αSynOs) in PD. Such oligomers appear to be particularly increased during the early pathological stages, targeting synapses at vulnerable brain regions leading to synaptic plasticity disruption, synapse loss, inflammation, excitation to inhibition imbalance and cognitive impairment. Absence of TauOs at synapses in individuals with strong AD disease pathology but preserved cognition suggests that mechanisms of resilience may be dependent on the interactions between soluble oligomers and their synaptic targets. In this review, we will discuss the current knowledge about the interactions between soluble oligomers and synaptic dysfunction in patients diagnosed with AD and PD, how it affects excitatory and inhibitory synaptic transmission, and the potential mechanisms of synaptic resilience in humans. Full article

(1) Background: With unknown causes and no effective treatment available, Alzheimer’s disease (AD) places enormous pressure on families and society. Our previous study had shown that Ebselen at a high concentration (10.94 μM) improved the cognition of triple-transgenic AD (3×Tg-AD) mice and alleviated the related pathological indicators but showed toxicity to the mice. Here, we dedicated to study the therapeutic effect and molecular mechanism of Ebselen at a much lower concentration on 3×Tg-AD mice. (2) Methods: Various behavioral experiments were applied to detect the behavioral ability of mice. Western blot, thioflavin T staining and a transmission electron microscope were used to evaluate the pathology of AD mice. The mitochondrial membrane potential and respiration were assessed with the corresponding assay kit. (3) Results: Ebselen remarkably increased cognitive ability of AD mice, eliminated β-Amyloid (Aβ) oligomers and recovered the synaptic damage in AD mice brain. In addition, the destroyed mitochondrial morphologies and function were repaired by Ebselen through ameliorating mitochondrial energy metabolism, mitochondrial biogenesis and mitochondrial fusion/fission balance in N2a-SW cells and brain tissues of AD mice. (4) Conclusions: This research indicated that Ebselen might exert its therapeutic effect via protecting mitochondria in AD. Full article

Alzheimer’s Disease (AD) is a neurodegenerative disorder that is characterized clinically by progressive cognitive decline and pathologically by the β-sheet rich fibril plaque deposition of the amyloid-β (Aβ) peptide in the brain. While plaques are a hallmark of AD, plaque burden is not correlated with cognitive impairment. Instead, Aβ oligomers formed during the aggregation process represent the main agents of neurotoxicity, which occurs 10–20 years before patients begin to show symptoms. These oligomers are dynamic in nature and represented by a heterogeneous distribution of aggregates ranging from low- to high-molecular weight, some of which are toxic while others are not. A major difficulty in determining the pathological mechanism(s) of Aβ, developing reliable diagnostic markers for early-stage detection, as well as effective therapeutics for AD are the differentiation and characterization of oligomers formed throughout disease propagation based on their molecular features, effects on biological function, and relevance to disease propagation and pathology. Thus, it is critical to methodically identify the mechanisms of Aβ aggregation and toxicity, as well as describe the roles of different oligomers and aggregates in disease progression and molecular pathology. Here, we describe a variety of biophysical techniques used to isolate and characterize a range of Aβ oligomer populations, as well as discuss proposed mechanisms of toxicity and therapeutic interventions aimed at specific assemblies formed during the aggregation process. The approaches being used to map the misfolding and aggregation of Aβ are like what was done during the fundamental early studies, mapping protein folding pathways using combinations of biophysical techniques in concert with protein engineering. Such information is critical to the design and molecular engineering of future diagnostics and therapeutics for AD. Full article

Amyloidosis is a common pathological event in which proteins self-assemble into misfolded soluble and insoluble molecular forms, oligomers and fibrils that are often toxic to cells. Notably, aggregation-prone human islet amyloid polypeptide (hIAPP), or amylin, is a pancreatic hormone linked to islet β-cells demise in diabetics. The unifying mechanism by which amyloid proteins, including hIAPP, aggregate and kill cells is still matter of debate. The pathology of type-2 diabetes mellitus (T2DM) is characterized by extracellular and intracellular accumulation of toxic hIAPP species, soluble oligomers and insoluble fibrils in pancreatic human islets, eventually leading to loss of β-cell mass. This review focuses on molecular, biochemical and cell-biology studies exploring molecular mechanisms of hIAPP synthesis, trafficking and degradation in the pancreas. In addition to hIAPP turnover, the dynamics and the mechanisms of IAPP–membrane interactions; hIAPP aggregation and toxicity in vitro and in situ; and the regulatory role of diabetic factors, such as lipids and cholesterol, in these processes are also discussed. Full article

Significant research on Alzheimer’s disease (AD) has demonstrated that amyloid β (Aβ) oligomers are toxic molecules against neural cells. Thus, determining the generation mechanism of toxic Aβ oligomers is crucial for understanding AD pathogenesis. Aβ fibrils were reported to be disaggregated by treatment with small compounds, such as epigallocatechin gallate (EGCG) and dopamine (DA), and a loss of fibril shape and decrease in cytotoxicity were observed. However, the characteristics of intermediate products during the fibril disaggregation process are poorly understood. In this study, we found that cytotoxic Aβ aggregates are generated during a moderate disaggregation process of Aβ fibrils. A cytotoxicity assay revealed that Aβ fibrils incubated with a low concentration of EGCG and DA showed higher cytotoxicity than Aβ fibrils alone. Atomic force microscopy imaging and circular dichroism spectrometry showed that short and narrow protofilaments, which were highly stable in the β-sheet structure, were abundant in these moderately disaggregated samples. These results indicate that toxic Aβ protofilaments are generated during disaggregation from amyloid fibrils, suggesting that disaggregation of Aβ fibrils by small compounds may be one of the possible mechanisms for the generation of toxic Aβ aggregates in the brain. Full article

Amyloid-β 42 peptide (Aβ_1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer’s disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment. Full article

Proteinopathy and excessive production of reactive oxygen species (ROS), which are the principal features observed in the Alzheimer’s disease (AD) brain, contribute to neuronal toxicity. β-amyloid and tau are the primary proteins responsible for the proteinopathy (amyloidopathy and tauopathy, respectively) in AD, which depends on ROS production; these aggregates can also generate ROS. These mechanisms work in concert and reinforce each other to drive the pathology observed in the aging brain, which primarily involves oxidative stress (OS). This, in turn, triggers neurodegeneration due to the subsequent loss of synapses and neurons. Understanding these interactions may thus aid in the identification of potential neuroprotective therapies that could be clinically useful. Here, we review the role of β-amyloid and tau in the activation of ROS production. We then further discuss how free radicals can influence structural changes in key toxic intermediates and describe the putative mechanisms by which OS and oligomers cause neuronal death. Full article

Amyloid-β (Aβ) 1-40 and 1-42 peptides are key mediators of synaptic and cognitive dysfunction in Alzheimer’s disease (AD). Whereas in AD, Aβ is found to act as a pro-epileptogenic factor even before plaque formation, amyloid pathology has been detected among patients with epilepsy with increased risk of developing AD. Among Aβ aggregated species, soluble oligomers are suggested to be responsible for most of Aβ’s toxic effects. Aβ oligomers exert extracellular and intracellular toxicity through different mechanisms, including interaction with membrane receptors and the formation of ion-permeable channels in cellular membranes. These damages, linked to an unbalance between excitatory and inhibitory neurotransmission, often result in neuronal hyperexcitability and neural circuit dysfunction, which in turn increase Aβ deposition and facilitate neurodegeneration, resulting in an Aβ-driven vicious loop. In this review, we summarize the most representative literature on the effects that oligomeric Aβ induces on synaptic dysfunction and network disorganization. Full article