Search Results (12,021)

The search for new compounds capable of inhibiting the activity of enzymes involved in the development of neurodegenerative diseases, including Alzheimer’s disease, has attracted continuing interest for many years. Natural isothiocyanates and their synthetic analogs, as well as compounds containing a 1,3,5-triazine core, constitute a group of molecules with complex mechanisms of action involving multiple molecular targets. Although literature data confirm the activity of both isothiocyanates and s-triazines, these two active fragments have not yet been combined, and it remains unclear whether a synergistic effect can be achieved. In this study, 11 novel isothiocyanate–triazine conjugates, consisting of a 1,3,5-triazine core substituted with aliphatic or cyclic secondary amines and a phosphorus analogue of isothiocyanate [6-(isothiocyanatohexyl)phosphonate)ethyl], were synthesized with yields of 46–80%. The pharmacokinetic profiles and parameters related to Lipinski’s rule of five were determined for all compounds. All compounds were evaluated as inhibitors of acetylcholinesterase (AChE) and β-secretase (BACE1). Compound 1i showed the highest inhibitory activity against AChE (IC₅₀ = 0.182 ± 0.02 µM), while compound 1b exhibited the strongest inhibition of BACE1 (IC₅₀ = 8.48 ± 2.18 µM). To explore the potential of these multifunctional derivatives, plausible enzyme-ligand binding models were proposed based on molecular docking simulations. Full article

Background/Objectives: Cognitive stimulation and cognitive training are used as non-pharmacological approaches to support people living with Alzheimer’s disease, but Alzheimer-specific evidence is dispersed across heterogeneous intervention formats. This scoping review mapped structured cognitive stimulation and training interventions evaluated in people with mild-to-moderate Alzheimer’s disease and summarized the cognitive, emotional, functional, and follow-up outcomes reported. Methods: The review was conducted using the Joanna Briggs Institute methodology and reported according to PRISMA-ScR. PubMed, SciELO, PEDro, LILACS, and Google Scholar were searched on 24 February 2025 for studies published between January 2015 and 24 February 2025 in English, Portuguese, or Spanish. Intervention studies were eligible. Two reviewers independently screened records and charted data, with disagreements resolved by a third reviewer. Results: Of 352 records identified, five studies involving 245 participants were included. Interventions comprised virtual-reality cognitive stimulation, conventional cognitive training, group reminiscence therapy, a multicomponent music–reminiscence–reality-orientation intervention, and computerized cognitive training. In the limited technology-assisted evidence, statistically significant changes were reported in global cognition or selected memory, language, attention, and executive outcomes. Conventional cognitive training showed signals of improvement in initiative and temporary stabilization of memory, whereas reminiscence-based interventions primarily reported changes in depressive and neuropsychiatric symptoms. Where longer follow-up was available, benefits diminished over time. Conclusions: The mapped evidence suggests that structured cognitive stimulation and training may produce short-term, outcome-specific benefits in mild-to-moderate Alzheimer’s disease. Given the small and heterogeneous evidence base, these findings represent modality-related patterns within the included studies and should not be interpreted as evidence of comparative effectiveness. Full article

Background/Objectives: Beginning in mid-life, age-related cognitive decline may negatively affect overall hearing health. Thus, understanding the relationship between hearing and cognition is of critical importance. Although the relationship has received considerable attention, and numerous theories have been posited to explain it, questions remain. Research indicates that 50% of older Americans grapple with severe hearing loss, affecting their daily communication, while Alzheimer’s disease, a prevailing cause of dementia, affects approximately 11% of Americans aged 65 or older. The Lancet Commission underscores hearing loss as a leading modifiable risk factor for dementia, contributing up to 7% of the risk. The purpose of this study was to advance our understanding of the specific domains of hearing and cognition that are related, thus informing theory and clinical practice. Methods: Participants were 99 older adults (mean age = 73 years) recruited from the 10-year Indicators of Cognitive Change study. Measures of peripheral hearing sensitivity (four-frequency pure-tone average [PTA4]) and auditory processing (Dichotic Sentence Identification [DSI]) were used to predict performance on multiple measures from the Montreal Cognitive Assessment (MoCA) and Cogstate Brief Battery (CBB). Results: DSI emerged as a significant predictor across both MoCA and CBB, surpassing the predictive power of PTA4. Surprisingly, relationships between hearing and cognitive measures differed for MoCA domains versus CBB subtests, highlighting the complexity of this association. Conclusions: The ability to separate and identify competing auditory information may be necessary components of healthy cognitive function. In clinical practice, assessment of binaural auditory processing may provide an early indicator of cognitive vulnerability in older adults. Full article

Background: Due to the rise in Alzheimer disease (AD) and AD-related dementias (AD/ADRD) in an aging population, millions of caregivers will be at risk for physical and mental health decline. As those they care for already have physical and cognitive impairment, it is crucial that caregivers maintain health-promoting behaviors. Because regular physical activity (PA) prevents functional loss and improves physical health and well-being, understanding how to help caregivers adopt and sustain PA despite unique time, caregiving, and self-efficacy barriers is a pressing public-health priority. Existing health-promoting interventions among dementia caregivers, including PA, have demonstrated limited success. To overcome the fragmentation and slow synthesis of behavioral science evidence, the Human Behavior-Change Project advocates theoretical grounding, systematic mapping of intervention components (e.g., behavior change techniques [BCTs]) using standardized taxonomies, and explicit specification of mechanisms of behavior change (MoBCs). Objective: To examine the limited success of health-promotion interventions among dementia caregivers we aimed to conduct a narrative review to synthesize evidence from interventions that evaluated PA in dementia caregivers across three domains: (1) use of behavioral theory to inform intervention design, (2) specification of BCTs, and (3) identification and measurement of MoBCs. Methods: Two scientific databases were searched to identify representative studies and reviews, using key terms including “physical activity”, “intervention”, “dementia”, and “caregiver” from inception to July 2025. Results: Seven primary intervention trials and six reviews were selected for inclusion. Gaps across the domains were identified to inform priority areas for future research. Conclusions: There is a need to develop tailored, theory-driven PA interventions that target empirically supported BCTs and MoBCs to improve dementia caregivers’ health and well-being. Full article

Alzheimer’s disease (AD) is the leading cause of dementia and a heterogeneous neurodegenerative disorder characterized by amyloid-β (Aβ) and tau pathology, impaired proteostasis, neurovascular dysfunction, maladaptive glial and immune responses, and synaptic dysfunction. Human genetic evidence supports an upstream role for Aβ. Anti-Aβ monoclonal antibodies substantially reduce amyloid burden and modestly slow clinical decline in early symptomatic AD. Continued decline despite plaque removal is consistent with ongoing downstream tau pathology, glial responses, and neuronal injury. This narrative review examines AD mechanisms, biomarkers, and therapeutic prospects from a geroscience perspective and applies the eight hallmarks of neurodegenerative diseases as an analytical framework. Advances in blood-based biomarkers, particularly plasma phosphorylated tau 217, may improve biological detection, but their clinical value depends on assay performance, intended use, and patient context. Gut dysbiosis and gut–brain communication are considered separately as candidate systemic modifiers because causal evidence in humans remains insufficient. The hallmarks are overlapping analytical categories, not independent primary causes, and their therapeutic relevance depends on disease stage and pathway activity. Future studies should establish which preventive strategies and biomarker-guided, stage-matched combination therapies improve clinically meaningful outcomes and identify the patients most likely to benefit. Full article

Background: Alterations in glutamatergic homeostasis have been implicated in Alzheimer’s disease, but the relationship between total hippocampal tissue glutamate and Alzheimer-like molecular alterations remains unclear. This study evaluated the early neuroprotective potential of gentisic acid (GA) and erucic acid (EA) in an intracerebroventricular streptozotocin (icv-STZ)-induced rat model of sporadic Alzheimer-like pathology. Methods: Sixty-four female Sprague–Dawley rats were randomly assigned to eight groups: control, sham, STZ, STZ + GA (100 or 200 mg/kg/day), STZ + EA (25 or 50 mg/kg/day), and STZ + memantine (10 mg/kg/day). Treatments began immediately after STZ and continued orally for 21 days. Behavioral performance was assessed by Morris water maze and passive avoidance tests. Total hippocampal tissue glutamate was quantified by LC–MS/MS. Neuronal degeneration was assessed histopathologically, whereas tau, amyloid-β, and AChE immunoreactivity and tau-, APP-, and AChE-related in situ hybridization signals were evaluated. Results: Compared with controls, STZ-treated rats exhibited poorer behavioral performance, higher total hippocampal tissue glutamate, greater neuronal degeneration, and increased molecular signals. GA and EA administration was associated with attenuation of these alterations, with generally stronger effects at higher doses. EA at 50 mg/kg/day showed the lowest mean total hippocampal tissue glutamate among treatment groups. GA at 200 mg/kg/day and EA at 50 mg/kg/day showed the most consistent preservation across behavioral, histopathological, and molecular endpoints. Conclusions: Early GA and EA administration was associated with neuroprotective effects in the icv-STZ model. Because treatment began immediately after STZ administration, the findings support early or preventive neuroprotection rather than reversal of established Alzheimer-like pathology. Total tissue glutamate measurements neither distinguish extracellular glutamate nor directly demonstrate glutamate-mediated excitotoxicity. Full article

Dihydroquercetin (DHQ), a powerful antioxidant and regulator of cellular metabolism, was proposed for therapy of neurodegenerative disorders. Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) are serious neurodegenerative disorders with oxidative stress as an overlapping feature and unmet therapeutic needs. To date, few studies have explored the efficacy of DHQ in animal models of genetically driven neurodegeneration. Here, APPswe/PS1dE9 (APP/PS1) mice and their wild-type (WT) littermates were orally administered DHQ (0.6 mg/kg/day) for four months, starting at eight months of age. At the age of 12 months, behavioral evaluation was performed, followed by brain staining with Congo red for amyloid plaque scoring and immunohistochemical analysis of GFAP-positive cells for the assessment of astrogliosis. Malondialdehyde (MDA) levels in the prefrontal cortex were studied as a marker of oxidative stress. Second, two-month-old FUS[1-359]-Tg mice, which recapitulate the hallmarks of ALS, received DHQ for 1.5 months and were investigated for general physiological parameters, the onset of paralysis, motor functions, and density of motor neurons in the spinal cord. DHQ-treated APPswe/PS1dE9 mutants displayed a decrease in amyloid plaque density of small size (≤100 μm) in the cortex and thalamus, had normalized MDA levels, improved conditioned taste aversion and Y-maze learning, and ameliorated anxiety measures, whereas their hippocampus-dependent step-down and pellet displacement performance remained impaired. In the second study, DHQ-treated FUS[1-359]-Tg mice showed rescued density of spinal cord neurons, normalized liquid and diet intake, and improved coat state, while the onset of paralysis and motor scores were not significantly ameliorated. Thus, chronic administration of low doses of DHQ exerted neuroprotective effects in both AD and ALS genetic models, which partially translated to reduced manifestations of these diseases. Full article

RNA-binding proteins (RBPs) are a large class of proteins that form biological condensates to facilitate their functions. Chronic stress, such as occurs in neurodegenerative diseases, stimulates persistent accumulation of particular RBP condensates as part of the translational stress response, termed stress granules (SGs). These persistent SGs serve as a nidus for aggregation of RBPs to form pathologies that appear in neurodegenerative diseases, such as the occurrence of Tar DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis. Many of the RBPs that accumulate in SGs are also associated with mutations that are linked to neurodegenerative diseases. The microtubule-associated protein tau is the major intracellular pathology that occurs in Alzheimer’s disease. Tau is phosphorylated with stress, whereupon it functions to regulate SG biology; conversely, SGs serve as a crucible for the accumulation of toxic oligomeric tau. The regulation of stress by tau is an inherent part of biology that normally occurs during development and hibernation; however, with aging it becomes pathological, possibly because of the reduced proteostasis associated with aging. Full article

Gut microbial metabolism links intestinal ecology with systemic physiology and neural pathology, but its effects vary across disease stage, tissue compartment, and host background. This review uses Alzheimer’s disease (AD) as the principal model and compares selected features with Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Across the AD continuum, fermentation-related changes appear in prodromal cohorts, whereas broader alterations in amino acid products, host–microbial co-metabolites, bile acids, and lipids accompany mild cognitive impairment and dementia. These group-level patterns do not constitute a fixed patient trajectory. Microbial production, intestinal absorption, hepatic conversion, renal clearance, barrier integrity, and tissue-specific receptors jointly determine biological exposure. Experimental studies connect short-chain fatty acids and indole derivatives with epithelial and neuroimmune homeostasis, while imidazole propionate, trimethylamine N-oxide, selected kynurenine products, and remodeled bile acid pools engage vascular, inflammatory, amyloid, or tau-related pathways. Cerebral pathology can also remodel the intestinal ecosystem, creating reciprocal feedback. Apolipoprotein E4 modifies lipid handling, vascular permeability, and immune responses, helping to explain why comparable metabolic profiles may carry different consequences among individuals. Translation therefore requires more than a change in community composition. Trials must verify microbial function, metabolite target engagement, AD biomarker response, and clinical benefit in appropriately stratified participants. Shared pathways in PD and ALS provide comparison points, but disease-specific cells, proteinopathies, and treatment exposures constrain direct transfer of AD-derived targets. Full article

Tau pathology is a hallmark feature of Alzheimer’s disease (AD) and is tightly associated with clinical manifestations. No disease-modifying therapy is currently available for AD, partly due to prominent interspecies differences in tau expression patterns between rodents and primates. To facilitate the investigation of primate-specific tau pathology, we developed an in vitro platform using monkey (Macaca fascicularis) brain slice cultures (BSC) that preserve native three-dimensional tissue architecture and maintain functional networks closely mirroring in vivo conditions. We systematically evaluated various adeno-associated virus (AAV) serotypes and promoter combinations to achieve efficient transgenic tau expression. Our data confirm that the monkey BSC system is highly amenable to AAV-mediated gene delivery, exhibiting robust transduction of glial cells with minimal cytotoxicity and allowing for the examination of glial pathology induced by disease-associated proteins. Notably, this platform is applicable to both juvenile and aged specimens, enabling comparative analyses of age-dependent susceptibility to pathological insults. Following overexpression of mutant human tau, we observed time-dependent tau pathology development within 2–4 weeks post-infection, including hyperphosphorylation and aggregation. This in vitro primate model offers a unique opportunity to dissect primate-specific pathological events. Furthermore, the scalability and reproducibility of this system render it ideally suited for drug screening, providing a more translationally relevant preclinical bridge between rodent models and human clinical trials. Full article

Introduction: Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder involving ROS and ferroptosis. MXene, a 2D material, functions as both a drug carrier and ROS scavenger. Butylphthalide (NBP), a neuroprotective agent, suffers from poor aqueous solubility and bioavailability. This study synthesized Ti₂C@BSA-NBP, a novel MXene nanocomposite, to enhance NBP delivery and therapeutic efficacy for AD. Materials and Methods: Ti₂C@BSA-NBP was synthesized via self-assembly and amidation reaction, and characterized by multiple techniques. In vitro, ROS-scavenging capacity, mitochondrial function, and ferroptosis markers were assessed in H₂O₂-injured cells. In vivo efficacy was evaluated in an AD mouse model via behavioral, histopathological, and biochemical analyses. Results: The nanocomposite exhibited robust ROS-scavenging activity in vitro, significantly attenuating ROS, restoring mitochondrial function, and reversing ferroptosis markers. In vivo, Ti₂C@BSA-NBP ameliorated learning/memory deficits, partially repaired neuronal morphology, and suppressed neuroinflammation. Mechanistically, it downregulated ACSL4 and Aβ overexpression while restoring GPX4 inhibition. Discussion: Ti₂C@BSA-NBP exerts synergistic neuroprotection through MXene-mediated ROS clearance and NBP-mediated multi-target regulation, counteracting oxidative stress, ferroptosis, and neuroinflammation. Conclusions: Ti₂C@BSA-NBP is a promising multifunctional nanoplatform integrating antioxidant activity, enhanced drug delivery, and ferroptosis modulation for AD therapy. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaques, neurofibrillary tau tangles, neuroinflammation, and progressive cognitive decline. Beyond these classical pathological features, emerging evidence implicates microbial dysbiosis as a contributing factor, with the gut and oral microbiomes currently providing the strongest evidence for microbiome AD associations. In contrast, the ocular microbiome represents a biologically plausible but largely unexplored candidate whose potential contribution to AD pathogenesis remains hypothetical and requires rigorous investigation. The ocular surface shares embryological, anatomical, and functional connections with the central nervous system, and the retina has emerged as a non-invasive window into neurodegenerative brain changes. Bacterial taxa detected in ocular specimens, including Cutibacterium acnes and Acinetobacter johnsonii, overlap with those reported in some studies of AD brain tissue, prompting speculation about an ocular–brain microbial interface. However, this overlap does not establish microbial trafficking, and no direct evidence currently supports the proposition that ocular microorganisms translocate to, colonize, or contribute causally to AD brain pathology. This review critically appraises the existing evidence, graded by methodological rigor and evidence strength, across gut, oral, nasal, ear, and ocular microbiome compartments. We address the substantial methodological challenges inherent in low-biomass microbiome research, emphasize the importance of distinguishing contamination artifacts from biological signals, and delineate the evidence gaps that separate association from causation. We conclude by proposing a research framework that places the ocular microbiome as an emerging hypothesis warranting experimental validation, rather than an established contributor to AD. Full article

Alzheimer’s disease (AD) is increasingly recognized as a disorder involving profound mitochondrial dysfunction. Although photobiomodulation (PBM) has shown neuroprotective efficacy in experimental AD models, whether restoration of mitochondrial architecture is mechanistically required for these effects remains unknown. Here, we investigated the role of mitochondrial network remodeling in PBM-mediated neuroprotection in primary mouse hippocampal neurons exposed to amyloid-β (Aβ). Neurons were treated for 24 h with oligomeric Aβ_1–42 and irradiated with 808 nm PBM (100 mW/cm², 30 J/cm²). Mitochondrial morphology was quantified using three-dimensional confocal microscopy and computational network analysis. Aβ exposure induced severe mitochondrial fragmentation and swelling, reflected by increased mitochondrial count and sphericity together with reduced mitochondrial volume, surface area, branch length, and network connectivity. These structural alterations were accompanied by elevated reactive oxygen species production, adenosine triphosphate depletion, membrane depolarization, and reduced neuronal viability. PBM significantly reversed these abnormalities, restoring mitochondrial network integrity and partially normalizing cellular bioenergetics and redox homeostasis. To determine whether mitochondrial dynamics contributes to PBM-induced effects, neurons in another experiment were pre-treated with the dynamin-related protein-1 (DRP-1) mitochondrial division inhibitor-1 (Mdivi-1). The physiological and morphological profiles of the Aβ + PBM + Mdivi-1 and Aβ + Mdivi-1 groups were found to be largely indistinguishable in this case, revealing that PBM failed to restore mitochondrial connectivity, cellular bioenergetics, or viability of neurons in the partially blocked fission–fusion machinery. These findings demonstrate that mitochondrial dynamics is essential for PBM-mediated neuroprotection and identify restoration of mitochondrial network integrity as a crucial mechanism linking PBM to improved neuronal bioenergetics, redox balance, and survival in AD. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder, which is characterized by several features, such as the deposition of amyloid β (Aβ) fibrils in the brain, leading to the formation of plaques and secondly tau-associated neurofibrillary tangles, resulting in the degeneration of the brain cells. Another feature of AD is mitochondrial dysfunction and oxidative stress, which are linked to the excessive production of reactive oxygen species (ROS). Under physiological conditions, ROS homeostasis is well controlled by the ROS generating system and the cellular antioxidant network. This antioxidant network is in part controlled by nuclear factor erythroid 2-related factor 2 (Nrf2), and its activation protects tissues against oxidative stress and chronic inflammation. Since oxidative stress, inflammation, and impaired proteostasis are significantly involved in the pathogenesis of AD, the KEAP1-Nrf2 system has emerged as a promising therapeutic target for the disease. Caenorhabditis elegans is an invaluable model organism among others for neurodegenerative disease research, due to its short life cycle, transparent body, and fully mapped nervous system and many transgenic C. elegans models have been developed to study different aspects of AD. This review attempts to provide comprehensive understanding of the molecular characteristics and pathological basis of AD, including the altered Nrf2-ARE signaling in AD and the molecular architecture and regulation of the Nrf2-SKN-1 pathway in C. elegans. An overview of plant-derived natural products and their effect on Nrf2/SKN-1 activation. Several classical and novel transgenic strains are described, translating findings from C. elegans to mammalian models and humans, including clinical translations and ongoing trials, as well as personalized medicinal approaches are discussed. Full article

Background: Over the last decade, numerous studies have investigated the administration of monoclonal anti-amyloid antibodies (AAAs) as a therapeutic approach in Alzheimer’s disease (AD). The purpose of this umbrella review is to summarize current knowledge concerning the efficacy and safety of FDA- and EMA-approved AAAs for AD, namely, lecanemab and donanemab. Methods: We conducted a literature search in the PubMed, Scopus, and Web of Science databases in English, focusing on systematic reviews and/or meta-analyses, assessed by AMSTAR 2, concerning clinical and imaging efficacy, i.e., cognitive improvement and reduction of beta-amyloid on PET scan, as well as safety, i.e., adverse events and amyloid-related imaging abnormalities (ARIA). The extracted review-level dataset was entered into SPSS Version 26 for descriptive statistical analysis. Results: This umbrella review included 11 systematic reviews and/or meta-analyses. Patients treated with lecanemab or donanemab showed statistically significant changes on cognitive scales such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB) (mean effect estimate −0.485, SD = 0.152, −0.70 to −0.34) and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), but most were below or around clinically meaningful thresholds. Lecanemab and donanemab showed a statistically significant decrease in amyloid PET outcomes, including centiloids or the standardized uptake value ratio. Both antibodies were linked to ARIA, including amyloid-related imaging abnormalities-edema (ARIA-E OR 8.32–12.26) and amyloid-related imaging abnormalities-hemorrhage (ARIA-H OR 2–5.77), especially in ApoEε4 carriers. Conclusions: Lecanemab and donanemab are biologically active drugs for the treatment of early AD, with cognitive benefits below or around the clinically meaningful threshold. They are, however, associated with increased ARIA risk. Their administration depends upon careful patient selection, shared decision-making, and clear communication regarding expectations. Full article