Amyloid-β Peptide Research Articles

Dual-ligand fluorescence microscopy enables chronological and spatial histological assignment of distinct amyloid-β deposits

Different types of deposits comprised of amyloid-β (Aβ) peptides are one of the pathological hallmarks of Alzheimer's disease (AD) and novel methods that enable identification of a diversity of Aβ deposits during the AD continuum are essential for understanding the role of these aggregates during the pathogenesis. Herein, different combinations of five fluorescent thiophene-based ligands were used for detection of Aβ deposits in brain tissue sections from transgenic mouse models with aggregated Aβ pathology, as well as brain tissue sections from patients affected by sporadic or dominantly inherited AD. When analyzing the sections with fluorescence microscopy, distinct ligand staining patterns related to the transgenic mouse model or to the age of the mice were observed. Likewise, specific staining patterns of different Aβ deposits were revealed for sporadic versus dominantly inherited AD, as well as for distinct brain regions in sporadic AD. Thus, by employing dual-staining protocols with multiple combinations of fluorescent ligands, a chronological and spatial histological designation of different Aβ deposits could be achieved. This study demonstrates the potential of our approach for resolving the role and presence of distinct Aβ aggregates during the AD continuum and pinpoints the necessity of using multiple ligands to obtain an accurate assignment of different Aβ deposits in the neuropathological evaluation of AD, as well as when evaluating therapeutic strategies targeting Aβ aggregates.

Impact of Antioxidants on Mechanical Properties and ROS Levels of Neuronal Cells Exposed to β-Amyloid Peptide.

This study aims to investigate the potential role of antioxidants in oxidative stress and its consequent impact on the mechanical properties of neuronal cells, particularly the stress induced by amyloid-beta (1-42) (Aβ42) aggregates. A key aspect of our research involved using scanning ion-conductance microscopy (SICM) to assess the mechanical properties (Young's modulus) of neuronal cells under oxidative stress. Reactive oxygen species (ROS) level was measured in single-cell using the electrochemical method by low-invasive Pt nanoelectrode. We investigated the effects of the low molecular weight antioxidant N-acetylcysteine (NAC) and the antioxidant enzyme superoxide dismutase 1 (SOD1) on the physiological and mechanical properties of neuronal cells using SICM. Using electrochemical method and SICM, NAC effectively reduces oxidative stress and restores Young's Modulus in SH-SY5Y cells exposed to hydrogen peroxide and Aβ42 oligomers. Our study first examined the influence of SOD1 on intracellular ROS levels in the presence of Aβ oligomers. The investigation into the effects of SOD1 and its nanoparticle form SOD1 on SH-SY5Y cells reveals impacts on mechanical properties and oxidative stress. The combined use of SICM and electrochemical measurements provided a comprehensive understanding of how oxidative stress, including that triggered by the Aβ oligomers affects the mechanical properties of cells.

Multifunctional Nitrogen-Doped Carbon Dots to Inhibit the Aggregation of Aβ Peptide and Depolymerize the Aβ Fibrils by Modulating Reactive Oxygen Species.

Multifunctional nitrogen-doped carbon dots (N-CDs) were synthesized, and the morphology, composition, and spectral properties of N-CDs were characterized by multiple characterization techniques. The inhibition of β-amyloid (Aβ) peptide aggregation and the destruction of the Aβ fibril structure by N-CDs were also studied. The conformational transition and morphology of Aβ42 in the presence of N-CDs were monitored by far-UV circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM). The results demonstrated that the prepared N-CDs could effectively inhibit Aβ42 peptide aggregation and depolymerize Aβ fibrils. Furthermore, the inhibition and disaggregation mechanism of existing Aβ42 fibrils by N-CDs was studied by electron paramagnetic resonance spectroscopy (EPR). The results showed that the modulation of reactive oxygen species (ROS) by N-CDs and multiple interactions between N-CDs and Aβ42 fibrils played a crucial part in restraining and reducing the aggregation of Aβ42. Our work demonstrates the therapeutic potential of N-CDs in suppressing Aβ42 peptide aggregation and destroying existing Aβ42 fibrils, which provides a new perspective strategy in the treatment of Alzheimer's disease (AD).

The role of carotenoids from red mamey fruit (Pouteria sapota) against amyloid-β monomers in Alzheimer's disease: Computational analysis and ADMET prediction.

Carotenoids, potent antioxidants in fruits and vegetables, have recently garnered attention for their potential therapeutic effects against neurodegenerative diseases. This study focuses on the interaction and anti-aggregation properties of conventional and unconventional carotenoids found in red mamey fruit, a nutraceutical fruit that is a rich source of these compounds. To assess computational the interaction between of amyloid-β (Aβ) peptide with a set of carotenoids and three carotenoids previously explored in experimental assays as well as to assess ADMET prediction of carotenoids selected by computational analysis results. We analyzed the interaction between these carotenoids and Aβ peptides using molecular docking, a key factor in Alzheimer's disease (AD) pathology. Selected carotenoids were compared with the reference compounds cryptocapsin (1), zeaxanthin (2), lutein (3), and cryptocapsin-5,6-epoxide (24), which previously demonstrated significant anti-aggregation activity against Aβ. Using SwissADME and ADMET Predictor® software to determine the pharmaceutical analysis prediction. Computational analysis identified (5R,8R)-sapotexanthin-5,8-epoxide (19) and (5S,8S)-cryptocapsin-5,8-epoxide (26) as the most promising candidates due to their strong binding affinity and potential anti-aggregation properties against Aβ. The pharmaceutical analysis identified compounds (5S,8S)-cryptocapsin-5,8-epoxide (26) and (5R,8R)-cryptocapsin-5,8-epoxide (28) as the most promising compounds. Our findings suggest that specific modifications in the carotenoid structure, particularly modifications in the type of epoxidation and stereochemistry, can significantly influence the biological activity of carotenoids and biopharmaceutical performance. These results provide valuable insights for future in vitro studies of most potential carotenoids (19 and 26) and the development of potential therapeutic agents for AD.

Synthesis and structural characterization BODIPY-based compounds for fluorescence sensing of β-amyloid aggregates

Alzheimer's disease (AD) is a neurodegenerative disorder associated with aging. According to the amyloid cascade hypothesis, the aggregation and accumulation of β-amyloid (Aβ) peptides in the brain as Aβ plaques is a critical process in the pathogenesis of AD. Among the existing diagnosis methods, fluorescence detection of β-amyloid (Aβ) has emerged as an alternative method due to its advantages such as real-time detection, low cost, not exposed to radiation, and high resolution for early diagnosis of Alzheimer's disease (AD). In this study, we designed and synthesized BODIPY-based compounds (BODIPY-3, BODIPY-4 and BODIPY-5) for the fluorescence detection of Aβ aggregates. In the fluorescence studies for detecting Aβ, BODIPY-5 with the squaric acid ester unit at the meso position of the BODIPY core showed a promising effect with an 11.7 μM Kd value.

Brain Amyloid-β Peptide Is Associated with Pain Intensity and Cognitive Dysfunction in Osteoarthritic Patients

Brain Amyloid-β Peptide Is Associated with Pain Intensity and Cognitive Dysfunction in Osteoarthritic Patients

Interaction of β-amyloid Peptide with Insulin Detemir Studied by Biolayer Interferometry and Molecular Modelling

Interaction of β-amyloid Peptide with Insulin Detemir Studied by Biolayer Interferometry and Molecular Modelling

Development of a novel radioiodinated compound for amyloid and tau deposition imaging in Alzheimer's disease and tauopathy mouse models

Non-invasive determination of amyloid-β peptide (Aβ) and tau deposition are important for early diagnosis and therapeutic intervention for Alzheimer's disease (AD) and non-AD tauopathies. In the present study, we investigated the capacity of a novel radioiodinated compound AD-DRK (123/125I-AD-DRK) with 50% inhibitory concentrations of 11 nM and 2 nM for Aβ and tau aggregates, respectively, as a single photon emission computed tomography (SPECT) ligand in living brains. In vitro and ex vivo autoradiography with 125I-AD-DRK was performed in postmortem human and two transgenic (Tg) mice lines with either fibrillar Aβ or tau accumulation, APP23 and rTg4510 mice. SPECT imaging of 123I-AD-DRK was performed in APP23 mice to investigate the ability of AD-DRK to visualize fibrillar protein deposition in the living brain. In-vitro autoradiogram of 125I-AD-DRK showed high specific radioactivity accumulation in the temporal cortex and hippocampus of AD patients and the motor cortex of progressive supranuclear palsy (PSP) patients enriched by Aβ and/or tau aggregates. Ex-vivo autoradiographic images also demonstrated a significant increase in 125I-AD-DRK binding in the forebrain of both APP23 and rTg450 mice compared to their corresponding non-Tg littermates. SPECT imaging successfully captured Aβ deposition in the living brain of aged APP23 mice. The present study developed a novel high-contrast SPECT agent for assisting the diagnosis of AD and non-AD tauopathies, likely benefiting from its affinity for both fibrillar Aβ and tau.

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer’s disease

BackgroundThe accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer’s disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored.MethodsWe generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL−G−F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background.ResultsBace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL−G−F/wt). Insoluble Aβ1–40 and Aβ1–42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL−G−F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1.ConclusionOur results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.

SERS-Based Microfluidic Bioscreening Platform for Selective Detection of β-Amyloid Peptides.

This study reports development of a microfluidic device for highly sensitive and selective detection of a β-amyloid peptide (Aβ1-42) in simulated cerebrospinal fluid, using surface-enhanced Raman spectroscopy (SERS). The device ensemble comprises a purine ligand (Pu) and its interaction with silver nanoparticles (AgNPs) to generate SERS hotspots. The low surface energy of the synthesized Pu ligand and high surface energy of AgNPs are utilized for the functionalization and formation of a Pu-AgNP SERS substrate. We have integrated a novel polydimethylsiloxane (PDMS) microfluidic device with Pu-AgNPs using a combination of photo- and soft lithography fabrication, sealed by thermal cross-linking with another layer of PDMS, to produce an effective screening platform for Aβ1-42. The SERS spectrum from the microfluidic device affords almost noise-free measurements, with excellent limit-of-detection values.

Membrane-Targeted Quantum Dot-Based BACE1 Activity Sensors for In Vitro and In Cellulo Assays.

The need for the development of specific and robust methodologies to elucidate the intricate pathological mechanisms of neurodegenerative diseases and discover effective treatments for prevention and remediation is evident. Alzheimer's disease, in particular, has become more prevalent as the global population has aged. β-Secretase, the β-site amyloid precursor protein cleaving enzyme (BACE1), is the protease that produces the β-amyloid peptide, which is considered one of the driving factors of Alzheimer's disease and an important target for treatment development. However, an understanding of its activity, modulation, and regulation is far from complete. This is in large part due to the complex nature of following its activity. Beyond the common requirements for all biosensors (ease of preparation and use), BACE1 probes also demand both stability at acidic pH and membrane localization. To overcome these hurdles, we exploit the modular self-assembly provided by fluorescent quantum dot (QD) sensors. As compared to other fluorophores, QDs provide enhanced fluorescence brightness and photostability, and their large surface area enables functionalization with peptide substrates together with targeting elements that localize the sensor to the areas of maximal BACE1 activity, all achieved through His-tag self-assembly. In vitro, the sensor demonstrated stability under acidic conditions, and using high-throughput plate reader assays, we determined BACE1 activity in-line with literature values and enabled the obtainment of the inhibitor constant of verubecestat, a small molecule inhibitor. The sensor was also transitioned to cellular experiments, where it demonstrated sensitivity to BACE1 activity and its modulation upon inhibitor treatment in a neuroblastoma cell line.

A Spectroscopic Study on the Amyloid-β Interaction with Clicked Peptide-Porphyrin Conjugates: a Vision Toward the Detection of Aβ Peptides in Aqueous Solution.

Alzheimer's disease (AD) is a multifactorial form of dementia mainly affecting people in the elderly, but no effective cure is available. According to the amyloid hypothesis the aggregation of Amyloid-β (Aβ) into oligomeric toxic species is believed to concur with the onset and progression of the disease heavily. By using a click chemistry approach, we conjugated a suitable designed peptide sequence to a metalloporphyrin moiety to obtain three hybrid peptide systems to be studied for their interaction with Amyloid-β peptides. The aim is to get new tools for the diagnosis and therapy in AD. The results described in this study, which were obtained through spectroscopic techniques (UV-Vis, CD, bis-Ans and intrinsic porphyrin Fluorescence), Microfluidics (GCI) and cell biology (MTT, Live cell imaging and flow cytometry), reveal interesting features about the structure-activity relationships connecting these conjugates with the interaction with Aβ, as well as on their potential use as sensing systems. In our opinion the data reported in this paper make the porphyrin-peptide conjugates highly compelling for further exploration as spectroscopic probes to detect Aβ biomarkers in biological fluids.

Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE-1 Inhibitors Against Alzheimer's Disease by In Silico, InVitro, and InVivo Studies.

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β-arrestin assay on GPR109A and qPCR on TRPM7 were also carried out. CBDA and CBGA are effective on both acetyl- and butyryl-cholinesterases (AChE/BuChE), as well as on β-secretase-1 (BACE-1) enzymes in a low micromolar range, and they also prevent aggregation of β-amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands. The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β-amyloid peptide. A recovery of the long-term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β-arrestin assay. Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti-AD MTDLs.

Synthesizing network pharmacology, bioinformatics, and in vitro experimental verification to screen candidate targets of Salidroside for mitigating Alzheimer's disease.

Alzheimer's disease (AD) is a neurological disorder leading to cognitive deficits. Salidroside (Sal), a primary bioactive ingredient extracted from the roots of Rhodiola rosea L., has potent neuroprotective effects in AD. However, studies on potential targets for Sal-anchored AD are limited. In this study, we combined network pharmacology, bioinformatics, and experimental validation to identify potential targets of Sal treating AD. First, we screened 10 pyroptosis-related genes (PRGs) in Sal and AD using public databases. Then, we used Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analysis to explore the biological functions of the shared PRGs (Sal and AD). This finding exhibited that pathways linked to inflammation, like the nucleotide oligomerization domain (NOD)-like receptors signaling pathway, are important for Sal to help fight AD. The GeneMANIA functional results subsequently revealed an association between AD and the processes of inflammasome complex and inflammatory response. Additionally, nine hub genes were identified in the protein-protein interaction network of these shared PRGs. Subsequent analysis of the genes and phenotypes confirmed that these nine hub genes were directly correlated with AD. Subsequently, an in vitro AD model was created using rat adrenal pheochromocytoma cell line (PC12) cells induced by amyloid β-peptide (Aβ) 25-35 (20µM). Sal significantly reduced the pyroptosis caused by Aβ 25-35 in PC12 cells and decreased the expression levels of IL-1β, CASP1, IL-18, PYCARD, and NLRP3. Furthermore, molecular docking and molecular dynamics simulations confirmed that Sal could stably bind to NLRP3. Druggability analysis revealed that Sal had excellent druggability. These results demonstrated that Sal could alleviate AD by targeting IL-1β, CASP1, IL-18, PYCARD, and NLRP3 to regulate the NLRP3-mediated pyroptosis signaling pathway.

Hemin, copper and amyloid-β: A medley involved in Alzheimer's disease. An interaction that fine regulates the reactivity

Metal ions have been shown to play a critical role in amyloid-β (Aβ) neurotoxicity and plaque formation which are key hallmarks of Alzheimer's disease. Amyloid-β peptides can bind both copper and hemin and this interaction modulates the redox chemistry of these metals. The characterization of the binding of hemin through UV–Vis spectroscopic titration with Aβ(4-16) shows a significantly higher affinity than that with Aβ(1-16). Also, the characterization of the hemin-catalyzed oxidation through different assays (peroxidase-like activity, ascorbate oxidation, HPLC-MS analysis of peptide oxidation) displays a greater reactivity in the presence of Aβ(4-16) when compared to that of Aβ(1-16). Since the Aβ(4-16) peptide sequence contains the typical amino-terminal copper and nickel binding motif (ATCUN), this leads to investigate the potential formation of ternary hemin/copper/Aβ(4-16) adducts. The evaluation of K1 and K2 (constants that regulate the formation of five-coordinated high-spin complex and of six-coordinated low-spin complex, respectively) for mixed systems indicates that the presence of copper stabilizes the 1:1 hemin-Aβ(4-16) species, partially hindering the formation of the low-spin complex. On the other hand, the formation of the ternary hemin/copper/Aβ(4-16) complex gives rise to a less efficient catalyst, resulting in a reduction of the overall oxidative reactivity. These results suggest that the reactivity of metal ions is finely modulated by the formation of complexes with amyloid peptides and this property is also regulated differently by the various in vivo relevant isoforms.

Lysine Acetyltransferase TIP60 Restricts Nerve Injury by Activating IKKβ/SNAP23 Axis-Mediated Autophagosome-Lysosome Fusion in Alzheimer's Disease.

The hyperphosphorylation of Tau protein is considered an important cause of neuronal degeneration in Alzheimer's disease (AD). The disruption of neuronal histone acetylation homeostasis mediated by Tip60 HAT is a common early event in neurodegenerative diseases, but the deeper regulatory mechanism on β-amyloid peptide (Aβ)-induced neurotoxicity and autophagic function in AD is still unclear. AD models were established both in APP/PS1 mice and Aβ1-42-treated SH-SY5Y cells. The Morris water maze test (MWM) was performed to examine mouse cognitive function. Neurological damage in the hippocampus was observed by hematoxylin-eosin (H&E), Nissl's, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and NeuN staining. Autophagosome-lysosome fusion was detected by immunohistochemistry, immunofluorescence, and Lyso-Tracker Red staining. Cell viability and apoptosis were evaluated by CCK-8 assay and flow cytometry. The molecular interactions were verified by co-immunoprecipitation (Co-IP), dual luciferase assays, and ChIP detections. The RNA and autophagy-lysosome-related proteins were assessed by Western blot and RT-qPCR. TIP60 overexpression improved cognitive deficits and neurological damage and restored the impairment of autophagy-lysosomes fusion invivo. Similarly, the upregulation of TIP60 in Aβ1-42-treated SH-SY5Y cells suppressed neuronal apoptosis and tau phosphorylation through the activating autophagy-lysosome pathway. Mechanistically, TIP60 activated IKKβ transcription by promoting SOX4 acetylation, thus leading to the translocation of SNAP23 to STX17-contained autophagosomes. Moreover, the protective roles of TIP60 in neuron damage were abolished by the inhibition of SOX4/IKKβ signaling. Collectively, our results highlighted the potential of the TIP60 target for AD and provided new insights into the mechanisms underlying neuroprotection in this disorder.

Circular RNA circ_0061183 regulates microglial polarization induced by airborne ultrafine particles in HMC3 cells via sponging miR-98-5p

Airborne ultrafine particulate matter (PM0.1) can enter the brain, induce microglia activation, and promote the development of Alzheimer’s disease (AD). Circular RNAs (circRNAs) are also involved in AD pathogenesis. However, the role of AD-related circRNAs in PM0.1-induced microglia activation remains unclear. Therefore, we explore cytotoxicity, microglia activation, and AD-associated circRNA expression in human microglial HMC3 cells treated with PM0.1, and further examined circRNA expression in mice and cognitively impaired individuals. The results revealed that PM0.1 exposure decreased cell viability, increased lactate dehydrogenase activity, caused microglia activation, elevated microglial M1 maker expression, downregulated microglial M2 maker expression, and reduced AD-related circ_0061183 expression in vitro. Functionally, circ_0061183 silencing enhanced microglia activation and microglial M1 polarization, but inhibited microglial M2 polarization. Mechanistically, circ_0061183 can bind to miR-98-5p to co-regulate M2 microglial-related IL10 expression, which may affect transforming growth factor-β signaling to regulate PM0.1-inhibited microglial M2 polarization. Moreover, circ_0061183 downregulation was observed in the brain of PM2.5-exposed mice and AD mice and in the blood of cognitively impaired individuals. Furthermore, circ_0061183 was positively related to mini–mental state examination scores and amyloid-β42 peptide expression in elderly individuals. Overall, the current work offers epigenetic insights into the regulatory mechanisms of circRNAs on microglial activation caused by environmental pollutants.

Efficacy and Mechanism of Schisandra chinensis Fructus Water Extract in Alzheimer's Disease: Insights from Network Pharmacology and Validation in an Amyloid-β Infused Animal Model.

Schisandra chinensis Fructus (SCF) is a traditional medicinal herb containing lignans that improves glucose metabolism by mitigating insulin resistance. We aimed to investigate the therapeutic potential and action mechanism of SCF for Alzheimer's disease (AD) using a network pharmacology analysis, followed by experimental validation in an AD rat model. The biological activities of SCF's bioactive compounds were assessed through a network pharmacology analysis. An AD rat model was generated by infusing amyloid-β peptide (Aβ) (25-35) into the hippocampus to induce Aβ accumulation. The AD rats were fed either 0.5% dextrin (AD-Con) or 0.5% SCF (AD-SCF group) in a high-fat diet for seven weeks. The rats in the normal/control group received an Aβ (35-25) infusion (no Aβ deposition) and were fed a control diet (Normal-C). Aβ deposition, memory function, inflammation, and glucose/lipid metabolism were evaluated. The network analysis revealed significant intersections between AD-related targets and bioactive SCF compounds, like gomisin A, schisandrin, and longikaurin A. Key AD genes prostaglandin-endoperoxide synthase-2 (PTGS2, cyclooxygenase-2) and acetylcholinesterase (AChE) were linked to SCF compounds. In the rats with AD induced by bilaterally infusing amyloid-β (25-35) into the hippocampus, the 0.5% SCF intake mitigated hippocampal amyloid-β deposition, neuroinflammation, memory deficits, and dysregulated glucose and lipid metabolism versus the AD controls. SCF reduced hippocampal AChE activity, inflammatory cytokine expression related to PTGS2, and malondialdehyde contents and preserved neuronal cell survival-related factors such as brain-derived neurotrophic factor and ciliary neurotrophic factor similar to normal rats. The neuroprotective effects validated the network analysis findings. SCF could be a potential AD therapeutic agent by activating the parasympathetic nervous system to reduce hippocampal oxidative stress and inflammation, warranting further clinical investigations of its efficacy.

ApoE: The Non-Protagonist Actor in Neurological Diseases.

Apolipoprotein E (APOE = gene, ApoE = protein) is a glycoprotein involved in the biological process of lipid transportation and metabolism, contributing to lipid homeostasis. APOE has been extensively studied for its correlation with neurodegenerative diseases, in particular Alzheimer's disease (AD), where the possession of the epsilon 4 (E4) allele is established as a risk factor for developing AD in non-familiar sporadic forms. Recently, evidence suggests a broad involvement of E4 also in other neurological conditions, where it has been shown to be a predictive marker for worse clinical outcomes in Parkinson's disease (PD), brain trauma, and disturbances of consciousness. The mechanisms underlying these associations are complex and involve amyloid-β (Aβ) peptide accumulation and neuroinflammation, although many others have yet to be identified. The aim of this review is to overview the current knowledge on ApoE as a non-protagonist actor in processes underlying neurodegenerative diseases and its clinical significance in AD, PD, acquired brain trauma, and Disorders of Consciousness (DoC). Ethical implications of genetic testing for APOE variants and information disclosure will also be briefly discussed.

Organic Chimeras based on Selenosugars, Steroids, and Fullerenes as Potential Inhibitors of the β-amyloid Peptide Aggregation.

The aggregation of β-amyloid peptide (Aβ) is associated with neurodegenerative diseases such as Alzheimer's disease (AD). Several therapies aimed at reducing the aggregation of this peptide have emerged as potential strategies for the treatment of AD. This paper describes the design and preparation of new hybrid molecules based on steroids, selenosugars, and [60]fullerene as potential inhibitors of Aβ oligomerization. These moieties were selected based on their antioxidant properties and possible areas of interaction with the Aβ. Cyclopropanations between C60 and malonates bearing different steroid and selenosugar moieties using the Bingel-Hirsch protocol have enabled the synthesis of functionalized molecular hybrids. The obtained derivatives were characterized by physical and spectroscopic techniques. Theoretical calculations for all the selenium compounds were performed using the density functional theory DFT/B3LYP-D3(BJ)/6-311G(2d,p) predicting the most stable conformations of the synthesized derivatives. Relevant geometrical parameters were investigated to relate the stereochemical behavior and the spectroscopic data obtained. The affinity of the compounds for Aβ-peptide was estimated by molecular docking simulation, which predicted an increase in affinity and interactions for Aβ for the hybrids containing the C60 core. In addition, parameters such as lipophilicity, polar surface area, and dipole moment were calculated to predict their potential interaction with membrane cells.