Search Results (2,242)

Neurodegenerative disorders, including Alzheimer’s disease (AD), are a growing problem in aging society. The amyloid cascade hypothesis has recently been questioned, and therapies based on it have not yielded the expected results. However, the role of amyloid-β (Aβ) in AD pathogenesis cannot be rejected. It appears that some of the key players in the pathogenesis of the disease are the soluble amyloid-β oligomers. Soluble amyloid-β oligomers have neurotoxic effects by disrupting intracellular Ca²⁺ homeostasis and impairing mitochondrial function. The glymphatic system is an important pathway for the removal of soluble amyloid forms from the brain. The decline in the activity of this system is observed in aging brains, which is correlated with the occurrence of Alzheimer’s disease, primarily among the elderly population. Therefore, the question arises as to whether the glymphatic system could be another potential target for therapeutic interventions in Alzheimer’s disease. In this regard, it is imperative to pay attention to the factors that contribute to the pathogenesis of Alzheimer’s disease and also impact the glymphatic system, such as sleep, physical activity, alcohol consumption, and supplementation with polyunsaturated fatty acids. The question remains whether the glymphatic system will become the key to treating Alzheimer’s disease. Full article

The matrix metalloproteinase (MMP) family includes several membrane-bound enzymes. Membrane-type 5 matrix metalloproteinase (MT5-MMP) is unique amongst the MMP family in being primarily expressed in the brain and during development. It is proposed to contribute to synaptic plasticity and is implicated in several pathologies, including multiple cancers and Alzheimer’s disease. In cancer, MT5-MMP expression has been correlated to cancer progression, but a distinct mechanistic role has yet to be uncovered. In Alzheimer’s disease, MT5-MMP exhibits pro-amyloidogenic activity, functioning as an η-secretase that cleaves amyloid precursor protein (APP), ultimately generating two synaptotoxic fragments, Aη-α and Aη-β. Several intracellular binding partners for MT5-MMP have been identified, and of these, N4BP2L1, EIG121, BIN1, or TMX3 binding to MT5-MMP results in a significant increase in MT5-MMP η-secretase activity. Beyond direct effects on APP, MT5-MMP may also facilitate APP trafficking to endosomal/lysosomal compartments and enhance proinflammatory responses. Overall, the substrate profile of MT5-MMP has not been well defined, and selective inhibitors of MT5-MMP have not been described. These advances will be needed for further consideration of MT5-MMP as a therapeutic target in Alzheimer’s disease and other pathologies. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, blood–brain barrier dysfunction, oxidative stress (OS), and neuroinflammation. Current treatments provide symptomatic relief, but do not halt the disease’s progression. OS plays a crucial role in AD pathogenesis by promoting Aβ accumulation. Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the antioxidant response, influencing genes involved in OS mitigation, mitochondrial function, and inflammation. Dysregulation of NRF2 is implicated in AD, making it a promising therapeutic target. Emerging evidence suggests that adherence to a Mediterranean diet (MD), which is particularly rich in polyphenols from extra virgin olive oil (EVOO), is associated with improved cognitive function and a reduced risk of mild cognitive impairment. Polyphenols can activate NRF2, enhancing endogenous antioxidant defenses. This study employs a computational approach to explore the potential of bioactive compounds in EVOO to modulate NRF2-related pathways in AD. We analyzed transcriptomic data from AD and EVOO-treated samples to identify NRF2-associated genes, and used chemical structure-based analysis to compare EVOO’s bioactive compounds with known NRF2 activators. Enrichment analysis was performed to identify common biological functions between NRF2-, EVOO-, and AD-related pathways. Our findings highlight important factors and biological functions that provide new insight into the molecular mechanisms through which EVOO consumption might influence cellular pathways associated with AD via modulation of the NRF2 pathway. The presented approach provides a different perspective in the discovery of compounds that may contribute to neuroprotective mechanisms in the context of AD. Full article

Background: There is growing interest in the potential role of manganese (Mn) in the development of Alzheimer’s Disease and related dementias (ADRD). Methods: In this nested pilot study of a ferroalloy worker cohort, we investigated the impact of chronic occupational Mn exposure on cognitive function through β-amyloid (Aβ) deposition and multi-omics profiling. We evaluated six male Mn-exposed workers (median age 63, exposure duration 31 years) and five historical controls (median age: 60 years), all of whom had undergone brain PET scans. Exposed individuals showed significantly higher Aβ deposition in exposed individuals (p < 0.05). The average annual cumulative respirable Mn was 329.23 ± 516.39 µg/m³ (geometric mean 118.59), and plasma Mn levels were significantly elevated in the exposed group (0.704 ± 0.2 ng/mL) compared to controls (0.397 ± 0.18 in controls). Results: LC-MS/MS-based pathway analyses revealed disruptions in olfactory signaling, mitochondrial fatty acid β-oxidation, biogenic amine synthesis, transmembrane transport, and choline metabolism. Simoa analysis showed notable alterations in ADRD-related plasma biomarkers. Protein microarray revealed significant differences (p < 0.05) in antibodies targeting neuronal and autoimmune proteins, including Aβ (25–35), GFAP, serotonin, NOVA1, and Siglec-1/CD169. Conclusion: These findings suggest Mn exposure is associated with neurodegenerative biomarker alterations and disrupted biological pathways relevant to cognitive decline. Full article

Alzheimer’s disease (AD) is increasingly recognized as a multifactorial disorder driven by a combination of disruptions in proteostasis and organelle communication. The 2020 Lancet commission reported that approximately 10 million people worldwide were affected by AD in the mid-20th century. AD is the most prevalent cause of dementia. By early 2030, the global cost of dementia is projected to rise by USD 2 trillion per year, with up to 85% of that cost attributed to daily patient care. Several factors have been implicated in the progression of neurodegeneration, including increased oxidative stress, the accumulation of misfolded proteins, the formation of amyloid plaques and aggregates, the unfolded protein response (UPR), and mitochondrial–endoplasmic reticulum (ER) calcium homeostasis. However, the exact triggers that initiate these pathological processes remain unclear, in part because clinical symptoms often emerge gradually and subtly, complicating early diagnosis. Among the early hallmarks of neurodegeneration, elevated levels of reactive oxygen species (ROS) and the buildup of misfolded proteins are believed to play pivotal roles in disrupting proteostasis, leading to cognitive deficits and neuronal cell death. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles is a characteristic feature of AD. These features contribute to chronic neuroinflammation, which is marked by the release of pro-inflammatory cytokines and chemokines that exacerbate oxidative stress. Given these interconnected mechanisms, targeting stress-related signaling pathways, such as oxidative stress (ROS) generated in the mitochondria and ER, ER stress, UPR, and cytosolic chaperones, represents a promising strategy for therapeutic intervention. This review focuses on the relationship between stress chaperone responses and organelle function, particularly the interaction between mitochondria and the ER, in the development of new therapies for AD and related neurodegenerative disorders. Full article

Recent findings highlight that Reelin, a glycoprotein involved in neural development, synaptic plasticity, and neuroinflammation, plays some specific roles in neurodegenerative disorders associated with aging, such as age-related macular degeneration (AMD) and Alzheimer’s disease (AD). Reelin modulates synaptic function and guarantees homeostasis in neuronal-associated organs/tissues (brain and retina). The expression of Reelin is dysregulated in these neurological disorders, showing common pathways depending on chronic neurogenic inflammation and/or dysregulation of the extracellular matrix in which Reelin plays outstanding roles. Recently, the relationship between AMD and AD has gained increasing attention as they share many common risk factors (aging, genetic/epigenetic background, smoking, and malnutrition) and histopathological lesions, supporting certain pathophysiological crosstalk between these two diseases, especially regarding neuroinflammation, oxidative stress, and vascular complications. Outside the nervous system, Reelin is largely produced at the gastrointestinal epithelial level, in close association with innervated regions. The expression of Reelin receptors inside the gut suggests interesting aspects in the field of the gut–brain–eye axis, as dysregulation of the intestinal microbiota has been frequently described in neurodegenerative and behavioral disorders (AD, autism, and anxiety and/or depression), most probably linked to inflammatory, neurogenic mediators, including Reelin. Herein we examined previous and recent findings on Reelin and neurodegenerative disorders, offering findings on Reelin’s potential relation with the gut–brain and gut–brain–eye axes and providing novel attractive hypotheses on the gut–brain–eye link through neuromodulator and microbiota interplay. Neurodegenerative disorders will represent the ground for a future starting point for linking the common neurodegenerative biomarkers (β-amyloid and tau) and the new proteins probably engaged in counteracting neurodegeneration and synaptic loss. Full article

Neuroinflammation is a key feature of Alzheimer’s disease (AD), and stem cell therapies have emerged as promising candidates due to their immunomodulatory properties. Neuro-Cells (NC), a combination of unmodified mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), have demonstrated therapeutic potential in models of central nervous system (CNS) injury and neurodegeneration. Here, we studied the effects of NC in APPswe/PS1dE9 mice, an AD mouse model. Twelve-month-old APPswe/PS1dE9 mice or their wild-type littermates were injected with NC or vehicle into the cisterna magna. Five to six weeks post-injection, cognitive, locomotor, and emotional behaviors were assessed. The brain was stained for amyloid plaque density using Congo red, and for astrogliosis using DAPI and GFAP staining. Gene expression of immune activation markers (Il-1β, Il-6, Cd45, Tnf) and plasticity markers (Tubβ3, Bace1, Trem2, Stat3) was examined in the prefrontal cortex. IL-6 secretion was measured in cultured human monocytes following endotoxin challenge and NC treatment. Untreated APPswe/PS1dE9 mice displayed impaired learning in the conditioned taste aversion test, reduced object exploration, and anxiety-like behavior, which were improved in the NC-treated mutants. NC treatment normalized the expression of several immune and plasticity markers and reduced the density of GFAP-positive cells in the hippocampus and thalamus. NC treatment decreased amyloid plaque density in the hippocampus and thalamus, targeting plaques of <100 μm². Additionally, NC treatment suppressed IL-6 secretion by human monocytes. Thus, NC treatment alleviated behavioral deficits and reduced amyloid plaque formation in APPswe/PS1dE9 mice, likely via anti-inflammatory mechanisms. The reduction in IL-6 production in human monocytes further supports the potential of NC therapy for the treatment of AD. Full article

Herpes simplex virus type 1 (HSV-1) is associated with eye infections. Specifically, the acute consequences of eye infections have been extensively studied. This review gathers information on possible collateral damage caused by HSV-1 in the retina, such as age-related macular degeneration (AMD), a neurodegenerative disease. The synthesis and accumulation of Amyloid-β peptide (Aβ) is a key hallmark in these types of pathologies. AMD is a disease of multifactorial origin, and viral infections play an important role in its development. It is known that once this virus has entered the eye, it can infect adjacent cells, thus having the ability to infect almost any cell type with great tropism. In the retina, retinal pigment epithelial (RPE) cells are primarily involved in AMD. This work reviews publications that show that RPE can produce Aβ, and once they are infected by HSV-1, the release is promoted. Also, all the information available in the literature that explains how these events may be interconnected has been compiled. This information is valuable when planning new treatments for multifactorial neurodegenerative diseases. Full article

A series of rivastigmine hybrids, incorporating rivastigmine fragments (RIV) and a set of different antioxidant scaffolds, were designed, synthesized, and evaluated as multifunctional agents for the potential therapy of Alzheimer’s disease (AD). In vitro bioactivity assays indicated that some compounds have very good antioxidant (radical-scavenging) activity. The compounds also displayed good inhibitory activity against cholinesterases, though the bigger-sized hybrids showed higher inhibitory ability for butyrylcholinesterase (BChE) than for acetylcholinesterase (AChE), due to the larger active site cavity of BChE. All the hybrids exhibited an inhibition capacity for self-induced amyloid-β (Aβ_1–42) aggregation. Furthermore, cell assays demonstrated that some compounds showed capacity for rescuing neuroblastoma cells from toxicity induced by reactive oxygen species (ROS). Among these RIV hybrids, the best in vitro multifunctional capacity was found for the caffeic acid derivatives enclosing catechol moieties (4AY5, 4AY6), though the Trolox derivatives (4AY2, 4BY2) presented the best cell neuroprotective activity against oxidative damage. Molecular-docking studies provided structural insights into the binding modes of RIV-based hybrids to the cholinesterases, revealing key interaction patterns despite some lack of correlation with inhibitory potency. Overall, the balanced multifunctional profiles of these hybrids render them potentially promising candidates for treating AD, thus deserving further investigation. Full article

The search for selective anticholinergic agents stems from varying cholinesterase levels as Alzheimer’s Disease progresses from the mid-to-late stage and from butyrylcholinesterase’s (BChE) role in β-amyloid plaque formation. While structure-based and pharmacophore-based virtual screening could search from large libraries in a short time, these methods do not consider dynamic features that result from a ligand’s inhibition of the enzyme and consequently may under- or overexaggerate enzyme selectivity of a given ligand. In this computational study, we probed the selectivity of representative secondary metabolite compounds against acetylcholinesterase and BChE through molecular dynamics simulations. The results were evaluated by analysis of the root mean squared deviation of ligand heavy atoms, the radius of gyration of each inhibited and uninhibited enzyme, root mean squared fluctuation of residues, intermolecular interaction energy, and linear interaction energy approximation of the Gibbs free energy of binding. These considerations further reveal the induced-fit characteristics contributing to ChE selectivity that are predominantly due to the greater flexibility of BChE’s active site gorge. Full article

Background: Mild Cognitive Impairment (MCI) represents an intermediate stage between normal cognitive aging and Alzheimer’s Disease (AD). Early and accurate identification of MCI is crucial for implementing interventions that may delay or prevent further cognitive decline. This study aims to develop a machine learning-based model for differentiating between Cognitively Normal (CN) individuals and MCI patients using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Methods: An ensemble classification approach was designed by integrating Extra Trees, Random Forest, and Light Gradient Boosting Machine (LightGBM) algorithms. Feature selection emphasized clinically relevant biomarkers, including Amyloid-β 42, phosphorylated tau, diastolic blood pressure, age, and gender. The dataset was split into training and held-out test sets. A probability thresholding strategy was employed to flag uncertain predictions for potential deferral, enhancing model reliability in borderline cases. Results: The final ensemble model achieved an accuracy of 83.2%, a recall of 80.2%, and a precision of 86.3% on the independent test set. The probability thresholding mechanism flagged 23.3% of cases as uncertain, allowing the system to abstain from low-confidence predictions. This strategy improved clinical interpretability and minimized the risk of misclassification in ambiguous cases. Conclusions: The proposed AI-driven ensemble model demonstrates strong performance in classifying MCI versus CN individuals using multimodal ADNI data. Incorporating a deferral mechanism through uncertainty estimation further enhances the model’s clinical utility. These findings support the integration of machine learning tools into early screening workflows for cognitive impairment. Full article

Amyloid-β (Aβ) aggregates are considered as the important factors of Alzheimer’s disease (AD). Multifunctional materials have shown significant effects in the diagnosis and treatment of AD by modulating the aggregation of Aβ and production of reactive oxygen species (ROS). Compared to traditional surgical treatment and radiotherapy, phototherapy has the advantages, including short response time, significant efficacy, and minimal side effects in disease diagnosis and treatment. Recent studies have shown that local thermal energy or singlet oxygen generated by irradiating certain organic molecules or nanomaterials with specific laser wavelengths can effectively degrade Aβ aggregates and depress the generation of ROS, promoting progress in AD diagnosis and therapy. Herein, we outline the development of photothermal therapy (PTT) and photodynamic therapy (PDT) strategies for the diagnosis and therapy of AD by modulating Aβ aggregation. The materials mainly include organic photothermal agents or photosensitizers, polymer materials, metal nanoparticles, quantum dots, carbon-based nanomaterials, etc. In addition, compared to traditional fluorescent dyes, aggregation-induced emission (AIE) molecules have the advantages of good stability, low background signals, and strong resistance to photobleaching for bioimaging. Some AIE-based materials exhibit excellent photothermal and photodynamic effects, showing broad application prospects in the diagnosis and therapy of AD. We further summarize the advances in the detection of Aβ aggregates and phototherapy of AD using AIE-based materials. Full article

Background/Objectives: Niemann-Pick disease Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 100,000 live births that belongs to the lysosomal storage diseases (LSDs). NPC is characterized by the abnormal accumulation of unesterified cholesterol, in addition to being an autosomal recessive inherited pathology, which belongs to LSDs. It occurs in 95% of cases due to mutations in the NPC1 gene, while 5% of cases are due to mutations in the NPC2 gene. In the cerebral cortex (CC), the disease shows lipid inclusions, increased cholesterol and multiple sphingolipids in neuronal membranes, and protein aggregates such as hyperphosphorylated tau, α-Synuclein, TDP-43, and β-amyloid peptide. Mitochondrial damage and oxidative stress are some alterations at the cellular level in NPC. Therefore, the aim of this work was to determine the gene expression profile in the CC of NPC1 mice in order to identify altered molecular pathways that may be related to the pathophysiology of the disease. Methods: In this study, we performed a microarray analysis of a 22,000-gene chip from the cerebral cortex of an NPC mutant mouse compared to a WT mouse. Subsequently, we performed a bioinformatic analysis in which we found groups of dysregulated genes, and their expression was corroborated by qPCR. Finally, we performed Western blotting to determine the expression of proteins probably dysregulated. Results: We found groups of dysregulated genes in the cerebral cortex of the NPC mouse involved in the ubiquitination, fatty acid metabolism, differentiation and development, and underexpression in genes with mitochondrial functions, which could be involved in intrinsic apoptosis reported in NPC, in addition, we found a generalized deregulation in the cortical circadian rhythm pathway, which could be related to the depressive behavior that has even been reported in NPC patients. Conclusions: Recognizing that there are changes in the expression of genes related to ubiquitination, mitochondrial functions, and cortical circadian rhythm in the NPC mutant mouse lays the basis for targeting treatments to new potential therapeutic targets. Full article

Alzheimer’s disease (AD) involves the accumulation of amyloid-β (Aβ) plaques, whose quantification plays a central role in understanding disease progression. Automated segmentation of Aβ deposits in histopathological micrographs enables large-scale analyses but is hindered by the high cost of detailed pixel-level annotations. Weakly supervised learning offers a promising alternative by leveraging coarse or indirect labels to reduce the annotation burden. We evaluated a weakly supervised approach to segment and analyze thioflavin-S-positive parenchymal amyloid pathology in AD and age-matched brains. Our pipeline integrates three key components, each designed to operate under weak supervision. First, robust preprocessing (including retrospective multi-image illumination correction and gradient-based background estimation) was applied to enhance image fidelity and support training, as models rely more on image features. Second, class activation maps (CAMs), generated by a compact deep classifier SqueezeNet, were used to identify, and coarsely localize amyloid-rich parenchymal regions from patch-wise image labels, serving as spatial priors for subsequent refinement without requiring dense pixel-level annotations. Third, a patch-based convolutional neural network, U-Net, was trained on synthetic data generated from micrographs based on CAM-derived pseudo-labels via an extensive object-level augmentation strategy, enabling refined whole-image semantic segmentation and generalization across diverse spatial configurations. To ensure robustness and unbiased evaluation, we assessed the segmentation performance of the entire framework using patient-wise group k-fold cross-validation, explicitly modeling generalization across unseen individuals, critical in clinical scenarios. Despite relying on weak labels, the integrated pipeline achieved strong segmentation performance with an average Dice similarity coefficient (≈0.763) and Jaccard index (≈0.639), widely accepted metrics for assessing segmentation quality in medical image analysis. The resulting segmentations were also visually coherent, demonstrating that weakly supervised segmentation is a viable alternative in histopathology, where acquiring dense annotations is prohibitively labor-intensive and time-consuming. Subsequent morphometric analyses on automatically segmented Aβ deposits revealed size-, structural complexity-, and global geometry-related differences across brain regions and cognitive status. These findings confirm that deposit architecture exhibits region-specific patterns and reflects underlying neurodegenerative processes, thereby highlighting the biological relevance and practical applicability of the proposed image-processing pipeline for morphometric analysis. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and chronic neuroinflammation. Emerging evidence suggests a crucial role of lipid signaling pathways in AD pathogenesis, particularly those mediated by autotaxin (ATX) and lysophosphatidic acid (LPA). ATX, an enzyme responsible for LPA production, has been implicated in neuroinflammatory processes, blood–brain barrier dysfunction, and neuronal degeneration. LPA signaling, through its interaction with specific G-protein-coupled receptors, influences neuroinflammation, synaptic plasticity, and tau pathology, all of which contribute to AD progression. This review synthesizes recent findings on the ATX/LPA axis in AD, exploring its potential as a biomarker and therapeutic target. Understanding the mechanistic links between ATX, LPA, and AD pathology may open new avenues for disease-modifying strategies. Full article