Search Results (201)

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two main neurodegenerative diseases and cause disability and death in patients worldwide. Neurodegeneration is characterized by a progressive loss of neuronal function and structure, causing enormous impairment in cognitive–motor function. Magnolol and honokiol are isomeric biphenyl neolignans and have exhibited neuroprotective activity in previous studies. Hence, we assessed and compared honokiol, magnolol, and mixtures of honokiol and magnolol in honokiol/magnolol molar ratios of 1:3, 1:1, and 3:1 in terms of their neurotoxicity, using the cell counting kit-8 (CCK-8) assay, and of their neuroprotective effect on intracellular reactive oxygen species (iROS) against amyloid-beta (Aβ)- and 1-methyl-4-phenylpyridinium ion (MPP⁺)-induced neurotoxicity in SH-SY5Y cells, using the 2′,7′-dichlorodihydrofluorescein diacetate (H₂DCF-DA) assay. The results showed that honokiol (H) and magnolol (M) at 0.1 μM and the mixtures of honokiol and magnolol in H/M ratios of 1:3, 1:1, and 3:1 at 0.0001 μM exhibited a significant neuroprotective effect of reducing iROS in SH-SY5Y cells where neurotoxicity was induced by Aβ- and MPP⁺ (p-value with respect to Aβ-treated cells < 0.005 and p-value with respect to MPP⁺-treated cells < 0.0001). Moreover, magnolol and honokiol possess antioxidant properties according to computational molecular analysis with Highest Occupied Molecular Orbital (HOMO)- Lowest Unoccupied Molecular Orbital (LUMO) prediction, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and Ferric Reducing Antioxidant Power (FRAP) assays. The mixtures of honokiol and magnolol exerted synergistic neuroprotective ability at all ratios while showing better antioxidation ability than that of pure magnolol alone but comparable to that of pure honokiol alone. Drug-likeness, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) prediction, and toxicity profiles showed that both compounds are promising neuroprotective agents and that one of the possible targeting mechanisms is the ROS-mediated oxidative stress pathway. Additional neuronal cell lines and in vivo models are required to determine similar effects or other protective mechanisms involving the neuroprotective ability of honokiol and magnolol. Full article

Alzheimer’s disease (AD) is characterized by cognitive decline and amyloid-β (Aβ)-related pathology. Non-rodent models that capture selected aspects of human AD remain limited. We established and characterized a human APP-driven, Aβ-related AD-like tree shrew model following AAV-mediated delivery of triple-mutant human amyloid precursor protein (hAPP-SLA) carrying the Swedish, Austrian, and London mutations by bilateral stereotaxic injection directed at CA1 coordinates. Adult tree shrews received bilateral AAV-hAPP-SLA injections directed at CA1 coordinates and were evaluated by bioluminescence imaging, behavioral testing, PCR, RT-qPCR, Western blotting, ELISA, and histopathology. Vector-associated reporter signals remained detectable for 6 months. The experimental group showed exogenous hAPP expression and reduced endogenous tsAPP expression, increased relative hippocampal Aβ₄₂ protein level, enhanced 4G8-reactive APP/Aβ-related signals, elevated total Aβ immunoreactivity, increased serum Aβ₄₂/Aβ₄₀ ratio, cytoarchitectural alterations, reduced Nissl staining, and Thioflavin S-reactive aggregate-associated signals. AT8 (Ser202/Thr205), GFAP, and Iba-1 immunoreactivity increased, whereas Synaptophysin and PSD-95 immunoreactivity was reduced. These changes were accompanied by reduced short-delay recognition-related performance and reduced social approach and social novelty preference. Aged tree shrews showed partly overlapping alterations. This model provides a non-rodent platform for studying human APP-driven Aβ-related pathology. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation and a breakdown of mitochondrial homeostasis. Vitamin K2 (VK2) has emerged as a potential neuroprotective agent, yet the specific molecular cascades linking its intervention to the restoration of mitochondrial integrity remain poorly understood. This study utilizes an AD Drosophila model to investigate the efficacy of VK2 and elucidates its multidimensional regulatory mechanisms. Behavioral analysis showed that VK2 significantly rescued locomotor impairments, improving both vertical climbing and horizontal walking performance. Crucially, VK2 intervention achieved a systemic rescue of mitochondrial health: transmission electron microscopy (TEM) confirmed the preservation of mitochondrial ultrastructure and cristae density, while biochemical assays demonstrated a robust recovery of bioenergetic markers, including ATP levels and the NAD⁺/NADH ratio. Furthermore, VK2 treatment stabilized the mitochondrial membrane potential (MMP) and effectively attenuated the accumulation of reactive oxygen species (ROS). To identify the molecular drivers of this recovery, an unbiased integration of human clinical transcriptomic data and network pharmacology prioritized the EGFR-Ras-ERK signaling axis as a central hub. In vivo validation confirmed that VK2 suppresses the pathological overactivation of this cascade. VK2 reduced EGFR phosphorylation in parallel with the effects observed for the EGFR inhibitor Gefitinib. Collectively, our findings show that VK2 ameliorates locomotor deficits and mitochondrial dysfunction in Aβ42-expressing flies and that these effects are associated with suppression of the EGFR-Ras-ERK signaling axis. Further studies are required to establish direct target engagement and pathway causality. Full article

Background: Blood-based biomarkers offer an accessible alternative to cerebrospinal fluid or positron emission tomography (PET) imaging for Alzheimer’s disease (AD) screening and diagnosis. This study evaluated the diagnostic performance of the fully automated HISCL plasma Aβ42/40 assay in a real-world clinical setting. Methods: We retrospectively enrolled 127 participants, stratified into cognitively normal (CN), mild cognitive impairment (MCI), AD, and Non-AD subgroups. Plasma Aβ42/40 levels were quantified using the HISCL and Simoa platforms. Additionally, plasma oligomerized Aβ (OAβ), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured. Results: The HISCL plasma Aβ42/40 ratio was significantly lower in the AD continuum (MCI + AD) compared to the CN subgroup (p < 0.001). The HISCL assay demonstrated robust diagnostic performance (AUC = 0.747), yielding a comparably higher AUC value compared to the Simoa Aβ42/40 ratio (AUC = 0.687). Although method comparison showed a proportional difference between HISCL and Simoa, the HISCL assay maintained high discriminative capability. Notably, integrating plasma GFAP and NfL with the HISCL Aβ42/40 ratio significantly enhanced the diagnostic accuracy (AUC = 0.823, p = 0.046). Method comparison between heparinized and EDTA plasma in the HISCL assay confirmed assay stability, showing a significant correlation and a regression slope near unity. Conclusions: The HISCL plasma Aβ42/40 assay demonstrates reliable diagnostic performance for identifying AD pathology in clinical practice, showing stability across sample types. Furthermore, its combination with neurodegeneration markers significantly improves predictive accuracy, supporting its utility as a robust screening tool and foundational component of future multimarker diagnostic panels. Full article

Background: Periodontitis affects approximately 7–11% of the global adult population in its severe forms and has been epidemiologically associated with cardiovascular, cardiometabolic, and neurodegenerative diseases. Low-grade chronic inflammation represents the unifying mechanism; however, an integrative framework connecting the oral cavity, the gut, and the brain into a single mechanistic continuum is lacking. Objective: This narrative review, conducted with structured (but non-systematic) elements and PRISMA-2020 style reporting used solely as a transparency tool, synthesizes current evidence on the oral–gut–brain axis. A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar (2000–March 2026), yielding 159 included studies after structured screening and eligibility assessment. The review focuses on: the molecular mechanisms by which periodontal dysbiosis may disrupt intestinal homeostasis and contribute to neuroinflammation; the role of salivary and intestinal biomarkers as monitoring tools for the entire axis; and emerging pharmacological opportunities targeting this tripartite pathway. Results: Periodontal pathogens, particularly Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum, have been detected ectopically in the gut and are associated with reduced tight junction protein expression and altered Firmicutes/Bacteroidetes ratios in preclinical and observational studies. These perturbations have been associated with increased blood–brain barrier (BBB) permeability, microglial activation, and amyloid-beta (Aβ) accumulation, although causal directionality in humans remains to be established. Salivary biomarkers (MMP-8, IL-1β, IL-6, BDNF) and intestinal biomarkers (short-chain fatty acids, calprotectin) reflect systemic inflammatory burden and offer potential for non-invasive screening. Conclusions: The oral–gut–brain axis provides a plausible unifying framework for understanding comorbidity among periodontal, cardiometabolic, and neurodegenerative diseases; however, current evidence is predominantly associative, and mechanistic extrapolation from preclinical models requires validation in longitudinal human studies. Salivary biomarkers may serve as candidate first-line tools for systemic risk assessment, and pharmacological interventions targeting this axis represent promising investigational directions warranting further clinical evaluation. Full article

Background and Objectives: Vascular dementia (VaD) and mixed dementia (MD) represent prevalent causes of cognitive decline in the elderly, as they share similar pathological pathways and clinical features. Distinguishing between these two conditions remains a challenge, due to their frequent clinical and neuroimaging overlap. Nevertheless, it is important from a prognostic perspective. Materials and Methods: The study comprised 114 participants, including patients with VaD (n = 33), MD (n = 26), Alzheimer’s disease (AD; n = 26), and 29 cognitively healthy controls (C). We evaluated routinely used cerebrospinal fluid (CSF) biomarkers (total tau, p-tau181, Aβ_1–42) and their ratios to assess inter-group differences, diagnostic accuracy, and correlations with cognitive score. Results: Patients with MD demonstrated significantly higher levels of t-tau and p-tau181, and lower levels of Aβ_1–42, compared to VaD (p < 0.004 for all analyses). With the exception of p-tau181/t-tau, all calculated ratios enabled differentiation between these groups. ROC analysis confirmed the high diagnostic accuracy of CSF Aβ_1–42 and t-tau (AUC 0.82 and 0.79 respectively) for detecting AD pathology in dementia patients. Furthermore, the t-tau/Aβ_1–42, p-tau181/Aβ_1–42 ratios were the most effective in differentiating AD-related from vascular pathologies (AUC 0.78 and 0.80 respectively), and in differentiating MD from VaD (AUC 0.79 and 0.77 respectively). A significant correlation was observed between CSF biomarkers (especially tau markers) and cognitive impairment severity. Conclusions: CSF biomarkers effectively differentiate mixed from vascular dementia by identifying underlying AD pathology independent of the clinical phenotype. This supports the use of CSF biomarkers in clinical practice to reveal the neurodegenerative component in patients with cerebrovascular disease, which is of fundamental importance for emerging disease-modifying treatment strategies in mixed neuropathologies. Full article

Background/Objectives: Alzheimer’s disease (AD) is a leading cause of dementia globally, yet standard diagnostic markers like cerebrospinal fluid (CSF) analysis and molecular imaging are invasive and resource-intensive. While artificial intelligence (AI)-based volumetric magnetic resonance imaging (MRI) offers a scalable and non-invasive alternative, data correlating these structural metrics with fluid biomarkers and cognitive status in Southeast Asian populations are scarce. This study addresses this critical gap by examining the within-cohort relationship between CSF biomarkers and regional brain volumes derived from AI-assisted MRI in Indonesian patients with clinically diagnosed AD, providing novel data for an underrepresented population. Methods: Twenty-one AD patients from three national referral hospitals in Indonesia underwent lumbar puncture for CSF biomarker analysis and 3 Tesla structural brain MRI. Brain volumes were analyzed using United Imaging Intelligence software, focusing on AD-relevant regions (hippocampus, entorhinal cortex, parahippocampus, precuneus, and posterior cingulate cortex [PCC]). Results: Spearman’s correlation revealed significant positive associations between CSF Aβ42 levels and several brain regions. Strong correlations were found with the right entorhinal volume indexed to intracranial volume (VICV) (r = 0.601, p = 0.004), right PCC VICV (r = 0.603, p = 0.004), right entorhinal volume (r = 0.533, p = 0.013), and right hippocampus VICV (r = 0.503, p = 0.020). Furthermore, MoCA-InA scores demonstrated highly significant positive correlations with CSF Aβ42 concentrations (r = 0.720, p < 0.001), right Hippocampus VICV (r = 0.703, p < 0.001), and right PCC VICV (r = 0.695, p < 0.001). No significant correlations were found between CSF pTau or the pTau/Aβ42 ratio and regional volumes. Conclusions: These results highlight the entorhinal cortex and PCC as early affected regions where CSF Aβ42 correlates with preserved volume, supporting their role as structural markers in early AD. The absence of pTau associations may reflect early-stage pathology or limitations of cross-sectional volumetry. In resource-limited settings, AI-assisted volumetric MRI demonstrates potential utility as a non-invasive tool for stratifying amyloid-associated brain atrophy and staging disease severity. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which amyloid-beta (Aβ) accumulation, oxidative stress (OS), and chronic inflammation drive synaptic dysfunction and cognitive decline. Molecular hydrogen (H₂) has emerged as a candidate neuroprotective gas with selective antioxidant and anti-inflammatory properties, although its efficacy in amyloid-driven pathology remains incompletely defined. In this study, 5xFAD transgenic mice harboring human amyloid precursor protein (APP) and presenilin-1 (PSEN1) mutations and age-matched C57BL/6 wild-type mice were exposed to 2% H₂ by inhalation for 1 h/day over 4 weeks. H₂ inhalation reduced hippocampal reactive oxygen species (ROS), increased systemic catalase activity, and enhanced hippocampal ATP levels. In serum, H₂ decreased tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β, restored IL-10, and partially normalized IL-13, shifting the peripheral environment toward a less pro-inflammatory profile. In the hippocampus, H₂ upregulated nuclear factor erythroid 2-related factor 2 (NRF2), attenuated nuclear factor kappa B (NF-κB) activation, reduced the BAX/BCL-2 ratio, preserved neuronal nuclei (NEUN) expression, and decreased hippocampal Aβ42 burden. Collectively, these findings indicate that H₂ inhalation confers multi-faceted neuroprotection in 5xFAD mice by restoring redox homeostasis, suppressing inflammation, improving mitochondrial function, and limiting Aβ accumulation. Full article

Objectives: This randomized, double-blind, placebo-controlled 12-week clinical trial evaluated the efficacy and safety of a standardized ethanol extract of purple perilla leaves (Perilla frutescens Britton var. acuta Kudo; PE) in adults with cognitive impairment. Methods: Subjects who met the inclusion criteria were randomly assigned in a 1:1 ratio to one of two groups and received PE (n = 50, 500 mg/day) or placebo (n = 50) for 12 weeks. The primary efficacy outcomes included cognitive function, which was assessed by the Korean mini-mental status examination–2 (K–MMSE–2) and the Alzheimer’s disease assessment scale–cognitive subscale (ADAS–Cog), and plasma amyloid β (Aβ) and brain-derived neurotrophic factor (BDNF) levels, which were measured as secondary biochemical markers. The safety biomarkers were also assessed before and after the intervention. Results: After 12 weeks of intervention, the K–MMSE–2 total score, the K–MMSE–2 subdomain scores (attention and calculation and language), the ADAS–Cog total score, and the ADAS–Cog subscale scores (word recall, commands, delayed word recall, naming, word recognition, and recall instructions) showed statistically significant between-group improvements compared with the placebo group. Improvements were observed in both groups, whereas the magnitude of cognitive enhancement was greater in the PE group, indicating an effect beyond placebo-related responses. No statistically significant between-group differences were observed in plasma Aβ or BDNF levels. The safety evaluation found no clinically significant changes. Conclusions: Twelve-week administration of PE significantly improved cognitive outcomes without safety concerns, suggesting its potential as a standardized botanical ingredient for supporting cognitive function in individuals with early cognitive impairment. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder affecting the central nervous system and is the most common form of dementia in the elderly. Current diagnostic methods are limited in the early and definitive diagnosis of the disease, necessitating the need for new and more reliable biomarkers. Circular RNAs (circRNAs) are non-coding, single-stranded, and highly stable RNA molecules commonly found in the eukaryotic transcriptome. Recent studies have shown that changes in the expression levels of circRNAs may play a role in AD pathogenesis. Furthermore, these molecules are considered as potential non-invasive biomarkers for early diagnosis of AD. In this study, we comprehensively assessed plasma levels of classical neurodegenerative biomarkers [amyloid-β42/amyloid-β40 (Aβ42/Aβ40) ratio, total Tau (tTau), and phosphorylated Tau (pTau)], as well as glial and inflammatory mediators, TAM receptor family members (Tyro3 and AXL), and the newly identified circular RNA molecule hsa_circ_003077. The findings revealed that the expression levels of TAM receptors were significantly increased, the Aβ42/Aβ40 ratio decreased, and both total Tau and phosphorylated Tau levels were significantly increased in AD patients. In the receiver operating characteristic (ROC) curve analysis performed to determine the diagnostic potential of hsa_circ_003077, the area under the curve (AUC) was 0.90 (95% CI: 0.82–0.97). This high AUC value suggests that hsa_circ_003077 may be a strong and novel biomarker candidate for the non-invasive diagnosis of AD. The data obtained confirmed the diagnostic efficacy of classical AD biomarkers and revealed that hsa_circ_003077 is a promising biomarker for early and accurate detection of the disease. However, in order to assess the transferability of these findings to clinical practice, confirmatory studies with larger sample groups are needed to ensure reproducibility of the results. Full article

Background/Objectives: Alzheimer’s disease (AD) has an irreversible disease course, making early intervention a key measure to delay disease progression. However, existing therapies are limited by weak brain-targeted delivery efficiency due to the blood–brain barrier (BBB) and low bioavailability of drugs, making it difficult to address the complexity of AD’s pathological mechanisms. Methods: Addressing these limiting factors, this research aims to develop an early AD intervention formulation with “high targeting, high bioavailability, and high biosafety.” Based on the principle of drug synergistic effects, this study employed the reverse solvent method and optimized the combination ratio of Ginsenoside Rg3 and Naringenin (Nar) to design and prepare a self-assembling nano-delivery system (Rg3-Nar-NPs, GNN). The study utilized intranasal administration to bypass the BBB through the direct pathway between the nasal mucosa and central nervous system. Results: This approach enabled targeted accumulation of the drug in brain lesion areas, significantly reducing Aβ deposition, oxidative stress, and inflammatory factor surges caused by early AD, thereby improving cognitive dysfunction in mice. Moreover, GNN demonstrated superior biosafety and bioavailability compared to the individual components. Through transcriptomic analysis, the study elucidated for the first time that GNN can activate the OXT/ERK/Fos pathway to break the malignant cycle of ROS–neuroinflammation, inhibiting the amplification effect of early AD pathological damage. Conclusions: This research provides new molecular targets and drug options for multi-target synergistic intervention of early AD, showing potential as a candidate strategy for precise early AD intervention and laying theoretical and experimental foundations for subsequent clinical translation. Full article

Chronic neuroinflammation is a prominent feature of several central nervous system disorders and contributes significantly to cognitive impairment. The present study aimed to investigate the effects of pretreatment with L-theanine (LT), aerobic exercise (ex), and their combination on cognitive deficits induced by subchronic lipopolysaccharide (LPS) administration in rats. Male Wistar rats were assigned to the following groups: control; veh-sed-LPS, sedentary (sed) rats treated with vehicle (veh) and LPS; LT-sed-LPS; veh-ex-LPS; and LT-ex-LPS. L-theanine treatment and/or treadmill running were administered for 5 weeks. Following these interventions, neuroinflammation was induced by LPS injections for 7 days, while the control group received veh treatment. Cognitive function was assessed using Y-maze, object recognition, and object location tests. Hippocampal cAMP response element-binding protein (CREB) phosphorylation status, β-amyloid (Aβ_1–42) accumulation, and pro-inflammatory cytokines (TNF-α, IL-1β) were measured by ELISA. Pretreatment with LT, ex, or their combination improved Y-maze performance and recognition memory, partly restoring the LPS-induced reduction in the pCREB/CREB ratio. Exercise, but not LT, reduced Aβ_1–42 levels and neuroinflammatory cytokine expression. Combined treatment produced additive benefits for some cognitive measures but not for spatial memory. These findings suggest that the prophylactic combination of LT and ex can partially attenuate cognitive impairments associated with subchronic neuroinflammation in this model. Full article

Clusterin is a chaperon protein that is involved in many physiological processes, including binding to beta-amyloid (Aβ). Recently, we showed that in Alzheimer’s disease (AD) model mice and human postmortem brains, there are elevated levels of methionine-oxidized clusterin in the disease state versus controls. These observations prompted us to investigate the possibility that elevated methionine-oxidized levels of clusterin in human blood plasma correlate with clinical diagnosis of both mild cognitive impairment (MCI) and AD stages. To achieve this goal, we have used a combination of Elisa kits for determining the total level of clusterin and methionine-oxidized clusterin in human blood plasma, enabling the quantification of a methionine-oxidized clusterin to total clusterin ratio. This ratio was correlated with the diagnostics of three groups of patients (normal controls (NL), MCI, and AD; with n = 44 per group). Accordingly, it was determined that there was a significant increase in the relative methionine-oxidized clusterin level in the MCI and AD groups compared to the controls. In conclusion, it is suggested that increased levels of methionine-oxidized clusterin in human blood plasma may serve as a potential marker for MCI and AD diagnosis. Full article

Major depressive disorder (MDD) has been associated with an increased risk of cognitive decline and neurodegenerative disorders like Alzheimer’s disease (AD), prompting interest in peripheral biomarkers related to amyloid metabolism as well as neuroaxonal and astroglial injury. However, evidence regarding circulating markers in MDD remains inconsistent. In this cross-sectional study, we simultaneously assessed plasma levels of amyloid-β peptides (Aβ40 and Aβ42), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in MDD patients and healthy controls (HC) using ultrasensitive single-molecule array (SIMOA) technology. Associations with clinical and cognitive scales were examined. Plasma concentrations of Aβ40 and Aβ42 were significantly lower in MDD patients, whereas no group differences were observed for NfL and GFAP, after correcting for age and sex. However, both Aβ peptides were not significantly associated with depressive symptom severity, whereas the Aβ42/Aβ40 ratio was negatively associated with anhedonia. NfL and GFAP levels were primarily influenced by age. In the absence of a reduced Aβ42/Aβ40 ratio, these findings suggest that reduced plasma Aβ levels in MDD may reflect systemic or metabolic factors associated with MDD, including lifestyle or treatment-related effects. Therefore, these findings should be interpreted with caution and further examined in longitudinal studies to prevent potential confounding factors. Full article

Identifying probiotics that modulate the gut–brain axis is vital for non-pharmacological Alzheimer’s disease (AD) therapy. Through a staged screening from transgenic Drosophila to a D-galactose/AlCl₃-induced murine model, Lactobacillus acidophilus LA4 and Lacticaseibacillus paracasei F5 were prioritized for their ability to improve climbing indices and reduce Aβ deposition and AChE activity. In AD mice, LA4 and F5 significantly ameliorated cognitive deficits and anxiety-like behaviors. Mechanistically, both strains reduced hippocampal Aβ_1–42 and p-Tau levels, inhibited AChE, suppressed pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and enhanced antioxidant enzymes (SOD, GSH-Px). 16S rRNA analysis revealed restored Firmicutes/Bacteroidetes ratios and enrichment of SCFA-producers (Muribaculaceae, Dubosiella). Metabolomics highlighted remodeled purine and arginine pathways, with strain-specific effects on primary bile acid biosynthesis/sphingolipid metabolism (LA4) and butanoate metabolism/nicotinate and nicotinamide metabolism (F5). Consequently, LA4 and F5 alleviate AD pathology by restructuring microbial and metabolic profiles, thereby mitigating neuroinflammation and oxidative stress. These findings confirm the potential of specific probiotics as functional food ingredients for the prevention and adjuvant treatment of neurodegenerative diseases. Full article