Search Results (108)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque deposition, neurofibrillary tau tangles, synaptic dysfunction, and progressive cognitive decline. AD is increasingly recognized as a condition in which chronic neuroinflammation actively shifts amyloid precursor protein (APP) processing toward the amyloidogenic pathway, driving Aβ production and accumulation rather than merely accompanying amyloid deposition. In this review, we examine the molecular cross-talk between inflammatory signalling and secretase regulation, highlighting how pro-inflammatory mediators promote amyloidogenic processing and contribute to downstream synaptic dysfunction. We discuss the major pathways linking glial activation to aberrant APP cleavage, including STAT3-dependent BACE1 upregulation, immune-mediated modulation of γ-secretase through IFITM3, and activation of the C/EBPβ/δ-secretase axis, which connects inflammatory stress to both amyloid and tau pathology. We further address the contribution of epigenetic mechanisms, particularly microRNA-mediated derepression of BACE1 and suppression of ADAM10, as well as SIRT3-related impairment of Aβ clearance. These interconnected processes establish a feed-forward pathogenic network in which neuroinflammation amplifies secretase imbalance, amyloidogenesis, and synaptic vulnerability. Finally, we discuss emerging multi-target therapeutic strategies aimed at modulating inflammatory signalling, restoring non-amyloidogenic APP processing, and preserving proteostatic and synaptic resilience. Collectively, this framework supports the view that targeting the inflammatory control of secretase activity may represent a biologically relevant strategy for disease modification in AD. Full article

Neurodegenerative diseases are a serious problem for modern society, and their treatment remains an important issue discussed by the scientific community. One of the promising potential directions for modulating neurodegenerative processes is the use of acylhydrazones, a class of compounds that combine different bioactive fragments linked by an acylhydrazone moiety. So far, the biological properties of these compounds have been proven. They show antibacterial, antiviral, antifungal, antiparasitic, anticancer, anti-inflammatory and antioxidant activity. Many research papers focus on designing acylhydrazones that will find use in the treatment of neurodegenerative diseases by inhibiting the enzymatic activity of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase 1 (BACE1) and monoamine oxidase (MAO), as well as inhibiting β-amyloid aggregation, exhibiting metal chelation and antioxidant properties. Recent studies have described the acylhydrazone-based dual (multi-target) inhibitors, which have demonstrated encouraging outcomes during in vitro evaluations. This review covers recent articles published in the years 2020–2025 and offers a comprehensive overview of the biological properties of the acylhydrazones and their multifunctional derivatives on neurodegenerative processes and/or neuroprotection, while emphasizing their universal nature, structural versatility and role as leading structures in the search for new drugs. Full article

A series of novel granatane–triazole hybrid molecules was designed, synthesized, and evaluated as dual acetylcholinesterase (AChE) and β-secretase 1 (BACE1) inhibitors. The compounds were obtained through a convergent synthetic route involving azide formation, triazole construction via dipolar cycloaddition, and final coupling with a granatane scaffold to give a pseudopelletierine (3-granatanone) analogue. In vitro assays demonstrated that all target compounds inhibited both AChE and BACE1. Molecular docking and molecular dynamics simulations revealed stable interactions with key catalytic residues, suggesting distinct binding modes compared to reference ligands. QSAR-based pharmacokinetic predictions indicated favorable blood–brain barrier permeability and compliance with key drug-likeness filters. These findings identify granatane–triazole hybrids as promising multi-target directed ligand (MTDL) candidates with potential for further optimization in the search for new anti-Alzheimer therapeutics. Full article

Alzheimer’s disease (AD) is a prevalent neurodegenerative condition that progressively impairs cognitive processes, particularly learning and memory. A key pathological feature of AD involves senile plaques mainly composed of β-amyloid (Aβ) peptides, generated via the amyloidogenic pathway from amyloid precursor protein (APP) through sequential β-secretase (BACE1) and γ-secretase cleavage, positioning BACE1 inhibition as a prime therapeutic target. In this study, we applied bioassay-guided fractionation of the butanol-soluble fraction from Dryopteris crassirhizoma rhizomes, previously reported to inhibit Aβ production, to isolate and characterize Aβ-lowering constituents. Through successive chromatographic steps, nine compounds were isolated and structurally classified into flavonoids, chromones, and phloroglucinols, including epicatechin (1), β-carboxymethyl-(-)-epicatechin (2), 7-methoxy-isobiflorin (3), biflorin (4), eriodictyol (5), noreugenin (6), phloroglucinols (butyrylphloroglucinol (7), 2-propionyl-4-methylphloroglucinol (8), and 2-butyryl-4-methylphloroglucinol (9) by comprehensive spectroscopic analysis (NMR, MS, UV, IR). These compounds were assessed for effects on sAPPβ and BACE1 (β-secretase) levels by Western blot, with Aβ production quantified via ELISA in a cellular AD model (APP-CHO cells). Compounds 5–9 significantly reduced sAPPβ and BACE1 expression while potently suppressing Aβ generation. These results demonstrate that diverse constituents from D. crassirhizoma rhizomes inhibited Aβ production through BACE1 suppression, highlighting their potential as natural lead compounds for AD prevention or therapy. Full article

The present study provides a comprehensive comparative evaluation of three Greek fig cultivars through integrated instrumental, computational, and chemometric approaches. Fresh fig peel and flesh samples were analyzed to determine total soluble solids, total phenolic and flavonoid content, as well as antioxidant and antiradical activities, complemented by attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy for structural profiling. Significant varietal and tissue-dependent differences were observed, with fig peel exhibiting higher levels of phenolic compounds and antioxidant activity compared to flesh. ATR-FTIR spectral patterns revealed the presence of characteristic functional groups associated with carbohydrates, phenolic compounds, carboxylic acids, and volatile compounds, reflecting the influence of variety, pollination requirements, and geographical origin. In parallel, to explore potential neuroprotective relevance, 30 phytochemicals reported in figs were subjected to molecular docking against human β-secretase 1 (hBACE1), a key enzyme in Alzheimer’s disease (AD) pathogenesis. Phenolic acids and flavonoids displayed favorable binding affinities and interaction profiles with the catalytic Asp32–Asp228 dyad and with the flap domain. A machine learning model (XGBoost) trained on known BACE1 inhibitors further classified all examined fig metabolites as active candidates. Collectively, these findings highlight Greek figs as chemically rich fruits with potential biological properties, supporting future targeted studies on their bioactive potential. Full article

Background/Objective: Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β plaques, derived from the amyloid precursor protein through sequential cleavage by β-secretase 1 (BACE-1) and γ-secretase. BACE-1 is therefore a key drug target for designing of selective inhibitors to avoid off-target effects associated with BACE-2 inhibition. The objective of this study was to design novel BACE-1 inhibitors using a structure-based drug design approach. Methods: A focused compound library was designed based on the SAR of N-(4-fluorophenyl)formamide derivatives. In silico ADME predictions were performed to assess pharmacokinetic suitability. Compounds showing favorable ADME profiles were subjected to molecular docking against the BACE-1 enzyme. The top-scoring hit, compound 9.7 (−5.48 (kcal/mol), was further evaluated using a 200 ns MD simulation to assess the stability of its binding interactions with BACE-1. Results: Designed compounds indicated acceptable physicochemical and ADME characteristics. Molecular docking identified compound 9.7 as exhibiting favorable binding interactions with binding pocket residues of BACE-1. The 200 ns MD simulation further confirmed the stability of the docked complex. MD simulations confirmed that 9.7 forms stable interactions with the catalytic residue ASP32 and key hydrophobic residues TRP115 and PHE108 of BACE-1. These important interactions are absent in the reference compound verubecestat. Conclusions: The multi-step computational analysis suggests that compound 9.7 is a promising and selective BACE-1 inhibitor. Its favorable ADME profile, favorable docking interactions, and stable MD simulation behavior highlight its potential as a hit compound for further optimization in the development of anti-Alzheimer’s agents. Full article

Alzheimer’s disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and neurodegeneration. Since the amyloid cascade hypothesis was proposed, Aβ has remained a central therapeutic target, with interventions aiming to reduce Aβ production, aggregation, or downstream toxicity. This review first outlines the historical development of the Aβ hypothesis and the two major APP processing pathways (α-cleavage and β-cleavage), highlighting the role of biomarkers in early diagnosis, patient stratification, and regulatory approval. We then summarize the development and clinical outcomes of anti-Aβ small-molecule drugs, including β-secretase inhibitors, γ-secretase modulators, Aβ aggregation inhibitors, receptor/synapse modulators, and metabolic or antioxidant modalities. We further review the progression of biologic therapies, with a particular focus on monoclonal antibodies, vaccines, and emerging gene-silencing strategies, such as small interfering RNA (siRNA) and antisense oligonucleotides. Finally, we discuss future perspectives, including next-generation biologics, multi-target approaches, optimized delivery platforms, and early-prevention strategies. Collectively, these efforts underscore both the challenges and opportunities in translating anti-Aβ therapies into meaningful clinical benefits for patients with AD. Full article

Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a critical deubiquitinating enzyme that is highly expressed in the central nervous system, where it participates in protein degradation and turnover as part of the ubiquitin–proteasome system (UPS). Convincing evidence supports the role of UCH-L1 dysfunction in several neurodegenerative disorders, given its unique position at the crossroad of several aetiopathogenic pathways, including those implicated in Alzheimer’s disease (AD) onset. Indeed, UCH-L1 depletion correlates with decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2), with consequent effects on neuroinflammation. Notably, UCH-L1 can affect the level of phosphorylated tau protein, thus contributing to the formation of neurofibrillary tangles (NFTs). In addition, UCH-L1 influences β-Secretase 1 (BACE1) expression, resulting in the abnormal accumulation of amyloid-β plaques in brain parenchyma. These findings underline UCH-L1’s centrality in maintaining the homeostasis of protein folding and aggregation, which are significantly impaired in AD and AD-related dementias. Given these assumptions, UCH-L1 is recognized as a potential biomarker for AD, highlighting its relevance in governing the fate of crucial pathological mediators of cognitive impairment and neurodegeneration. Herein, we contextualize the involvement of UCH-L1 in different dementia-associated pathways and summarize the state of the art of UCH-L1 as a biomarker for AD diagnosis. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)—a bioactive glycoside from Morus alba L.—present promising alternatives. This study investigated MsA’s neuroprotective potential using scopolamine-induced AD-like mice and N2a/APP695swe cells. In vivo, MsA significantly ameliorated cognitive deficits and neuronal loss, concurrently enhancing cholinergic neurotransmission through increased acetylcholine levels and inhibited acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) activities. MsA also upregulated neurotrophic factors (BDNF, CREB) in critical brain regions. In vitro, MsA restored cholinergic function, mitigated oxidative stress, and crucially reduced amyloid-β (Aβ) production by dual regulation of APP processing: promoting the non-amyloidogenic pathway via ADAM10 upregulation and inhibiting the amyloidogenic pathway via suppression of BACE1 and γ-secretase components. Mechanistically, these multi-target benefits were mediated by MsA’s activation of the PI3K/AKT pathway, which triggered downstream inhibitory phosphorylation of GSK3β—directly reduced tau hyperphosphorylation—and activation of CREB/BDNF signaling. Collectively, our findings demonstrate that MsA confers comprehensive neuroprotection against AD pathology by simultaneously targeting cholinergic dysfunction, oxidative stress, Aβ accumulation, tau phosphorylation, and impaired neurotrophic signaling, highlighting its strong therapeutic candidacy. Full article

β-secretase 1 (BACE1), known for its role in amyloid-β production associated with Alzheimer’s disease (AD), has also been suggested to be elevated in patients with Type 2 diabetes mellitus (T2DM). Notably, BACE1 could cleave the insulin receptor (InsR), leading to reduced InsR levels, which may impair insulin signaling and contribute to insulin resistance. Presently, we observed decreased InsR levels and impaired glucose disposal in the livers of mice with systemic overexpression of BACE1 (HUBC mice). This suggests that elevated BACE1 could contribute to insulin resistance by shedding membrane InsR. Additionally, mice fed a high-fat diet (HFD), a well-established model of T2DM, displayed increased BACE1 levels and decreased InsR. To further investigate whether inhibiting BACE1 could enhance insulin sensitivity and alleviate symptoms of diabetes, we treated HFD mice with the BACE1 inhibitor Elenbecestat. Remarkably, the administration of Elenbecestat restored InsR levels and improved their downstream signaling pathways, leading to increased insulin sensitivity and enhanced glucose tolerance. In summary, our findings suggest that inhibiting BACE1 can restore InsR expression and improve insulin-signaling sensitivity, ultimately resulting in enhanced diabetic phenotypes. Full article

A notion of the continuous production of amyloid-β (Aβ) via the proteolysis of Aβ-protein-precursor (AβPP) in Alzheimer’s disease (AD)-affected neurons constitutes both a cornerstone and an article of faith in the Alzheimer’s research field. The present Perspective challenges this assumption. It analyses the relevant empirical data and reaches an unexpected conclusion, namely that in AD-afflicted neurons, the production of AβPP-derived Aβ is either discontinued or severely suppressed, a concept that, if proven, would fundamentally change our understanding of the disease. This suppression, effectively self-suppression, occurs in the context of the global inhibition of the cellular cap-dependent protein synthesis as a consequence of the neuronal integrated stress response (ISR) elicited by AβPP-derived intraneuronal Aβ (iAβ; hence self-suppression) upon reaching certain levels. Concurrently with the suppression of the AβPP proteolytic pathway, the neuronal ISR activates in human neurons, but not in mouse neurons, the powerful AD-driving pathway generating the C99 fragment of AβPP independently of AβPP. The present study describes molecular mechanisms potentially involved in these phenomena, propounds novel approaches to generate transgenic animal models of AD, advocates for the utilization of human neuronal cells-based models of the disease, makes verifiable predictions, suggests experiments designed to validate the proposed concept, and considers its potential research and therapeutic implications. Remarkably, it opens up the possibility that the conventional production of AβPP, BACE enzymes, and γ-secretase components is also suppressed under the neuronal ISR conditions in AD-affected neurons, resulting in the dyshomeostasis of AβPP. It follows that whereas conventional AD is triggered by AβPP-derived iAβ accumulated to the ISR-eliciting levels, the disease, in its both conventional and unconventional (triggered by the neuronal ISR-eliciting stressors distinct from iAβ) forms, is driven not (or not only) by iAβ produced in the AβPP-independent pathway, as we proposed previously, but mainly, possibly exclusively, by the C99 fragment generated independently of AβPP and not cleaved at the γ-site due to the neuronal ISR-caused deficiency of γ-secretase (apparently, the AD-driving “substance X” predicted in our previous study), a paradigm consistent with a dictum by George Perry that Aβ is “central but not causative” in AD. The proposed therapeutic strategies would not only deplete the driver of the disease and abrogate the AβPP-independent production of C99 but also reverse the neuronal ISR and ameliorate the AβPP dyshomeostasis, a potentially significant contributor to AD pathology. Full article

Alzheimer’s disease (AD), a leading neurodegenerative disorder, is closely associated with the accumulation of amyloid-beta (Aβ) peptides in the brain. The enzyme β-secretase (BACE1), pivotal in Aβ production, represents a promising therapeutic target for AD. While bioactive peptides derived from food protein hydrolysates have neuroprotective properties, their inhibitory effects on BACE1 remain largely unexplored. In this study, we evaluated the inhibitory potential of protein hydrolysates from gliadin, whey, and casein proteins prepared using bromelain, papain, and thermolysin. Through in vitro and cellular assays, bromelain-hydrolyzed gliadin (G-Bro) emerged as the most potent BACE1 inhibitor, with an IC₅₀ of 0.408 mg/mL. G-Bro significantly reduced BACE1 expression and amyloid precursor protein (APP) processing in N2a/PS/APP cell cultures, suggesting its potential to attenuate Aβ aggregation. The unique peptide profile of G-Bro likely contributes to its inhibitory effect, with proline residues disrupting β-sheets, lysine residues introducing positive charges that hinder aggregation, hydrophobic residues stabilizing binding interactions, and glutamine residues enhancing solubility and stability. These findings highlight gliadin hydrolysates, particularly G-Bro, as potential natural BACE1 inhibitors with applications in dietary interventions for AD prevention. However, further studies are warranted to elucidate specific peptide interactions and their bioactivity in neural pathways to better understand their therapeutic potential. Full article

Background/Objectives: Diabetes mellitus (DM), a widespread endocrine disorder characterized by chronic hyperglycemia, can cause nerve damage and increase the risk of neurodegenerative diseases such as Alzheimer’s disease (AD). Effective blood glucose management is essential, and sitagliptin (SITG), a dipeptidyl peptidase-4 (DPP-4) inhibitor, may offer neuroprotective benefits in type 2 diabetes mellitus (T2DM). Methods: T2DM was induced in rats using nicotinamide (NICO) and streptozotocin (STZ), and biomarkers of AD and DM-linked enzymes, inflammation, oxidative stress, and apoptosis were evaluated in the brain. Computational studies supported the in vivo findings. Results: SITG significantly reduced the brain enzyme levels of acetylcholinesterase (AChE), beta-secretase-1 (BACE-1), DPP-4, and glycogen synthase kinase-3β (GSK-3β) in T2DM-induced rats. It also reduced inflammation by lowering cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). Additionally, SITG improved oxidative stress markers by reducing malondialdehyde (MDA) and enhancing glutathione (GSH). It increased anti-apoptotic B-cell lymphoma protein-2 (Bcl-2) while reducing pro-apoptotic markers such as Bcl-2-associated X (BAX) and Caspace-3. SITG also lowered blood glucose levels and improved plasma insulin levels. To explore potential molecular level mechanisms, docking was performed on AChE, COX-2, GSK-3β, BACE-1, and Caspace-3. The potential binding affinity of SITG for the above-mentioned target enzymes were 10.8, 8.0, 9.7, 7.7, and 7.9 kcal/mol, respectively, comparable to co-crystallized ligands. Further binding mode analysis of the lowest energy conformation revealed interactions with the critical residues. Conclusions: These findings highlight SITG’s neuroprotective molecular targets in T2DM-associated neurodegeneration and its potential as a therapeutic approach for AD, warranting further clinical investigations. Full article

Background: The goal of the current study was to investigate the inhibitory activity of six phenolic compounds, i.e., rosmarinic acid, gallic acid, oleuropein, epigallocatechin gallate (EGCG), 3-hydroxytyrosol, and quercetin, against β-site amyloid precursor protein cleaving enzyme-1 (BACE1), also known as β-secretase or memapsin 2, which is implicated in the pathogenesis of Alzheimer’s disease (AD). Methods and Results: The inhibitory potential against BACE1, molecular docking simulations, as well as neurotoxicity and the effect on the AD-related gene expression of the selected phenolics were tested. BACE1 inhibitory activity was carried out using the ELISA microplate assay via fluorescence resonance energy transfer (FRET) technology. Molecular docking experiments were performed in the human BACE1 active site (PDB code: 2WJO). Neurotoxicity of the compounds was carried out in SH-SY5Y, a human neuroblastoma cell line, by the Alamar Blue method. A gene expression analysis of the compounds on fourteen genes linked to AD was conducted using the real-time polymerase chain reaction (RT-PCR) method. Rosmarinic acid, EGCG, oleuropein, and quercetin (also used as the reference) were able to inhibit BACE1 with their respective IC₅₀ values 4.06 ± 0.68, 1.62 ± 0.12, 9.87 ± 1.01, and 3.16 ± 0.30 mM. The inhibitory compounds were observed to occupy the non-catalytic site of the BACE1. However, hydrogen bonds were found to be present between rosmarinic acid and EGCG and aspartic amino acid D228 in the catalytic site. Oleuropein and quercetin effectively suppressed the expression of PSEN, APOE, and CLU, which are recognized to be linked to the pathogenesis of AD. Conclusions: The outcomes of the work bring quercetin, EGCG, and rosmarinic acid to the forefront as promising BACE1 inhibitors. Full article

Accurate predictions of molecular properties are crucial for advancements in drug discovery and materials science. However, this task is complex and requires effective representations of molecular structures. Recently, Graph Neural Networks (GNNs) have emerged as powerful tools for this purpose, demonstrating significant potential in modeling molecular data. Despite advancements in GNN predictive performance, existing methods lack clarity on how architectural choices, particularly activation functions, affect training dynamics and inference stages in interpreting the predicted results. To address this gap, this paper introduces a novel activation function called the Sine Linear Unit (SLU), aimed at enhancing the predictive capabilities of GNNs in the context of molecular property prediction. To demonstrate the effectiveness of SLU within GNN architecture, we conduct experiments on diverse molecular datasets encompassing various regression and classification tasks. Our findings indicate that SLU consistently outperforms traditional activation functions on hydration free energy (FreeSolv), inhibitory binding of human β secretase (BACE), and blood brain barrier penetration (BBBP), achieving the superior performance in each task, with one exception on the GCN model using the QM9 data set. These results underscore SLU’s potential to significantly improve prediction accuracy, making it a valuable addition to the field of molecular modeling. Full article