Search Results (254)

Background:/ Over the past decade, increasing evidence has shifted attention from the brain to the gut microbiota (MB) as a source and site of systemic dissemination of amyloid-β (Aβ), an APP derivative responsible for plaque formation in the brains of Alzheimer’s disease (AD) patients. Furthermore, AD patients and APP/PS1 mice, a transgenic model of AD, exhibit dysbiosis. Objectives: Using APP/PS1 mice treated from 2 to 8 months of age, we studied ileal and colonic epithelial integrity, intestinal barrier (IB) integrity assessed through tight junction (TJ) protein expression, local immune system, the presence/increase in Aβ expression in enterocytes, and the protective effects of synbiotic treatment. Methods: The tissue was stained with Periodic Acid-Schiff and Alcian Blue to evaluate epithelial morphology and mucus production, and immunohistochemistry was performed to assess TJs, immune markers, and Aβ expression. Results: Our results demonstrate that colonic and ileal epithelium of 8-month-old APP/PS1 mice displays IB impairment in term of alterations of goblet cells staining and TJ protein expression and signs of immune involvement. The ileum was more severely affected, showing a reduced epithelial surface area, decreased lysozyme production, and fewer tuft cells. Long-term synbiotic treatment largely prevented APP/PS1 mouse changes and caused a significant increase in Aβ expression in all treated mice. Conclusions: These findings support the belief in early intestinal involvement in AD and highlight the potential of the microbiota as a target for early intervention aimed at modifying the progression to neurodegeneration. Increased epithelial Aβ labeling after treatment raises the possibility of intestinal management of Aβ, which requires further validation. Full article

Growing evidence suggests an important pathogenetic role of brain-specific gangliosides in the mechanisms underlying Alzheimer’s disease (AD), the most common form of dementia. Nutritional strategies targeting ganglioside sialylation—for example, through agglutinin-mediated modulation—have therefore attracted increasing research interest. In particular, wheat malt extract (WME), a food-derived source of wheat germ agglutinin (WGA) with high affinity for gangliosides, may influence molecular pathways involved in AD pathogenesis. Twelve-month-old female APPswe/PS1E9 transgenic mice, a model of AD, and wild-type (WT) littermates received WME or tap water for three weeks. Behavioral performance was subsequently assessed. Amyloid plaque burden and astrocyte activation were evaluated using Congo red staining and GFAP immunoreactivity, respectively. Gene expression of selected AD markers in the brain was quantified by RT–qPCR. Aged WT mice exhibited robust, region-specific molecular responses to WME, including upregulation of activity-dependent and synaptic plasticity genes (Arc, Egr1, Bdnf, Syp), enhancement of metabolic and insulin-related signaling (Pgc1a, Sirt1, Igf1r, Irs2), increased Cldn5 expression, and reduced pro-inflammatory Il1β expression. APP/PS1 mice exhibited limited response to WME, suggesting more persistent transcriptional signatures of synaptic impairment, metabolic dysregulation, and neuroinflammation than in WT mice. We found no significant effects of WME treatment on amyloid plaque density and behavior in APP/PS1 mice. No effects on astrocyte activation were observed in either group. These findings demonstrate that dietary WME counteracts abnormal behaviors and molecular changes in neuron plasticity, metabolic, and vascular markers under conditions of normal aging but fails to improve the hallmarks of AD pathology. This highlights the potential of WGA-containing nutrients as a preventive nutritional approach targeting pathogenic mechanisms of aging and, potentially, AD pathology. Full article

Alzheimer’s disease (AD) lacks effective disease-modifying therapies, and extracellular vesicles (EVs) derived from adipose-derived mesenchymal stromal cells (ADMSCs) have emerged as promising therapeutic candidates. In this study, we investigated the brain biodistribution and dose-dependent effects of intranasally administered ADMSC-EVs in female APP/PS1 mice, with age-matched wild-type mice and vehicle-treated transgenic mice serving as controls. EV biodistribution was assessed using PKH26 labeling, cognitive performance was evaluated using the Morris water maze, Y-maze, and novel object recognition tests, and hippocampal amyloid pathology and plasma AD-related biomarkers were analyzed. Intranasally delivered ADMSC-EVs rapidly reached multiple brain regions, including the hippocampus, improved learning and memory performance, and reduced hippocampal amyloid-β 1-42 (Aβ42) deposition and plaque burden. These effects followed a nonlinear dose–response pattern, with reduced efficacy at low doses and no additional benefits at high doses. Notably, partial behavioral and pathological benefits persisted after treatment cessation. Together, these findings show that intranasal ADMSC-EVs exert therapeutic effects in APP/PS1 mice and support the importance of dose optimization and post-treatment durability in the development of EV-based interventions for AD. Full article

Emerging evidence implicates metabolic dysfunction as a key contributor to Alzheimer’s disease (AD) pathogenesis. Fructose, a major component of modern diets, promotes systemic metabolic alterations; however, its direct impact on AD-related brain dysfunction remains poorly defined. Here, we investigated the effects of short-term fructose consumption on systemic metabolism, brain glucose handling, and cognitive performance in APP/PS1 transgenic mice. Six-month-old asymptomatic male mice received 15% fructose in drinking water for eight weeks, while controls received plain water. Fructose-fed APP/PS1 mice developed metabolic alterations consistent with early metabolic syndrome, including increased fasting glucose and dyslipidemia. These changes were accompanied by reduced cerebral glucose utilization, increased Aβ₄₂ accumulation, and impaired cognitive performance. In parallel, fructose intake enhanced neuroinflammatory markers, suggesting a coordinated disruption of metabolic and inflammatory pathways in the brain. Collectively, these findings support the idea that fructose consumption may exacerbate Alzheimer-like alterations linking systemic metabolic dysfunction to impaired brain glucose metabolism and neuroinflammation. This study provides mechanistic evidence supporting a role for dietary fructose as a modifiable risk factor in AD vulnerability. Full article

Alzheimer’s disease (AD) is increasingly recognized as a multisystem neurodegenerative disorder in which sensory dysfunction accompanies cognitive decline. As an accessible extension of the central nervous system, the retina provides a valuable window for investigating early neurodegenerative processes; however, the cellular mechanisms underlying AD-associated retinal pathology remain incompletely understood. Here, using the APP/PS1 mouse model, we systematically examined structural, functional, and glial alterations in the retina across disease stages. Despite robust age-dependent amyloid plaque accumulation in visual-related brain regions, no plaque-like β-amyloid (Aβ) deposits were detected in the retina even at advanced ages. Nevertheless, young APP/PS1 mice exhibited early thinning of inner retinal layers, impaired retinal electrophysiological responses, and reduced excitatory synaptic inputs to retinal ganglion cells (RGCs), preceding overt neuronal loss. These neuronal changes were accompanied by pronounced Müller glial activation, characterized by upregulation of gliosis markers and extensive morphological remodeling. Functional analyses further revealed dynamic alterations in glial homeostasis, including early elevation followed by age-dependent decline of glutamine synthetase activity, together with increased expression and disrupted perivascular polarity of aquaporin-4. Consistently, transcriptomic profiling of young AD retinas identified coordinated dysregulation of genes involved in amino acid metabolism, transport, and oxidative stress responses. Together, our findings identify Müller glial remodeling as an early feature of AD-associated retinal pathology that coincides with synaptic vulnerability of RGCs and occurs independently of local Aβ plaque deposition, highlighting retinal glia as potential early indicators and modulators of neurodegeneration. Full article

Alzheimer’s disease (AD) research has primarily focused on amyloid beta (Aβ) and tau protein; however, drug development targeting these two proteins has been disappointing. Therefore, there is an urgent need to explore the novel pathogenic mechanisms underlying AD. Recently, we found that expression of the K670N/M671L-mutated amyloid precursor protein (APP) in 293T cells significantly reduced membrane ferroportin (FPN) levels. Furthermore, 2-month-old APP/PS1 mice exhibited a marked decrease in membrane FPN levels, while total FPN expression and Aβ levels remained unchanged. Further studies revealed that features of ferroptosis were present in the brains of 2-month-old APP/PS1 mice, and that treatment with ferroptosis inhibitors or iron chelation significantly alleviated early pathological changes and cognitive impairment in these animals. In addition, supplementation with an APP–FPN binding peptide during the early phase ameliorated AD-related pathologies, including Aβ deposition, neuroinflammation, oxidative stress, and synapse-associated protein deficits, in APP/PS1 mice. Collectively, our findings suggest that APP mutations may contribute to early brain pathological changes and subsequent memory impairment in AD by downregulating membrane trafficking of FPN and inducing ferroptosis, thereby providing new molecular targets for drug development. Full article

The gut–brain axis is increasingly implicated in Alzheimer’s disease (AD) pathogenesis, but the potential correlation between AD-associated gut microbiota and central inflammation remains largely unclear. This study aimed to explore their correlative link, with a focus on changes and involvement of Th17 cell-related factors in the gut–brain axis. Healthy C57BL/6J mice were pretreated with antibiotics for 1 week to deplete the indigenous gut microbiota, followed by 2 weeks of fecal microbiota transplantation (FMT) using feces from APP/PS1 AD model mice. Hematoxylin–eosin (H&E) staining, ELISA, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), 16S rDNA sequencing, and correlation analysis were performed to evaluate ileal and central pathological changes, Th17 cell-related inflammatory mediators, ileal microbiota composition, and their potential correlations. The results demonstrated that AD-FMT significantly induced ileal inflammatory infiltration and central inflammation in recipient mice, which was accompanied by abnormal expression of Th17 cell-related indicators, elevated levels of Th17-associated inflammatory factors, upregulated RORγt mRNA expression, and perturbed ileal microbiota composition. Correlation analysis further suggested that specific ileal bacterial taxa were closely correlated with Th17 cell-related inflammatory factors. These findings suggest a potential correlation between AD-associated microbiota and central inflammation, possibly by regulating intestinal Th17 cell-related indicators and altering gut microbial composition. This study provides correlative evidence supporting the involvement of the gut–brain axis in AD-related pathogenesis, highlighting the link between gut microbiota, central inflammation and Th17-related factors. Full article

Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer’s disease (AD) mouse models, partly by upregulating apolipoprotein E (Apoe), a major AD genetic risk factor. However, the specific cellular contributions to these effects are unclear. Here, we used single-cell transcriptomic profiling to investigate cell subpopulation-specific responses to bexarotene, an RXR agonist, in APP/PS1 mice. Our analysis revealed that bexarotene activated cholesterol biosynthesis and lipid metabolism transcriptional programs in homeostatic astrocytes and oligodendrocytes. Astrocytes also upregulated neurodevelopmental genes, while oligodendrocytes and endothelial cells showed enhanced protein folding and cellular growth pathways. Bexarotene further modulated immune responses, promoting Aβ-responsive signatures in disease-associated microglia and reactive astrocytes while dampening pro-inflammatory responses in homeostatic microglia and endothelial cells. Furthermore, Apoe expression was significantly elevated across multiple cell types, especially in microglia and oligodendrocytes. Cell–cell communication analysis highlighted increased astrocyte-centered signaling, with APOE-driven pathways emerging as a prominent mediator. These findings clarify the molecular complexity of RXR-mediated regulation, revealing the cellular origins of bexarotene’s known effects as well as novel, cell-type-specific responses. This study provides mechanistic insights into RXR-targeted interventions and supports APOE-associated pathways as promising therapeutic targets in AD. Full article

Background/Objectives: Alzheimer’s disease (AD) involves amyloid-β (Aβ) deposition, oxidative stress, and neuroinflammation, leading to cognitive decline. Nobiletin, a citrus-derived polymethoxylated flavonoid, exerts antioxidant and anti-inflammatory effects. This study explored its neuroprotective mechanisms in the 5XFAD mouse model. Methods: Male 5XFAD and C57BL/6J mice received oral nobiletin (20 or 40 mg/kg/d) for 4 weeks. Cognitive function was assessed by the Y-maze test. Amyloid-β burden was quantified by Congo red staining and ELISA. Serum cytokine levels and antioxidant enzyme activities were measured by ELISA. Western blotting and RT-PCR were used to assess proteins and genes related to amyloidogenesis, inflammation (TLR4/MyD88/NF-κB), mitochondrial biogenesis (AMPK/SIRT1/PGC-1α), and synaptic plasticity (PI3K/Akt–CREB–BDNF). Results: Nobiletin improved working memory, reduced amyloid-β40/42 deposition, and downregulated APP, BACE1, and PS1 expression, while enhancing ADAM10 expression. It lowered serum IL-6, IL-1β, and TNF-α, increased SOD, CAT, and GPx activities, and suppressed TLR4/MyD88/NF-κB signaling. Furthermore, it activated AMPK/SIRT1/PGC-1α and NRF2 pathways, enhancing antioxidant defenses, and promoted PI3K/Akt–CREB–BDNF signaling, increasing PSD95 and synaptophysin. Conclusions: Nobiletin exerts strong neuroprotective and antioxidant effects by targeting multiple signaling cascades, mitigating amyloid pathology and neuroinflammation, and improving synaptic plasticity. It represents a promising therapeutic agent against AD. Full article

Background/Objectives: Alzheimer’s disease (AD) is a neurodegenerative disease for which there are no highly effective treatments, which highlights the need for novel therapeutics. Cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory and neuroprotective properties. Chronic CBD treatment (20 mg/kg and 50 mg/kg) reverses social recognition memory deficits of APP_Swe/PS1∆E9 (APP/PS1) transgenic mice; however, it does not produce effects on AD-relevant brain pathology. Methods: Here, we investigated whether chronic high-dose CBD treatment (i.e., 100 mg/kg intraperitoneally) in early symptomatic 7.5-month-old APP/PS1 males would reverse cognitive deficits while also influencing neuropathological markers relevant to AD. Mice were assessed for anxiety, recognition memory, and social and aggressive behaviours before carrying out neuropathological analyses of collected brain tissue. Results: Vehicle-treated APP/PS1 transgenic males demonstrated reduced aggressive behaviour and increased socio-positive behaviour. A moderate deficit in social recognition memory was restored by CBD. APP/PS1 mice also exhibited elevated cortical proBDNF levels under vehicle treatment, and hippocampal levels of TNF-α and IL-1β were reduced in all APP/PS1 mice. AD transgenic mice exhibited no changes in soluble or insoluble Aβ₄₂ levels or PPARγ isoforms. Conclusions: This study found that high-dose CBD restored a moderate social recognition memory deficit. However, CBD did not have marked effects on AD-relevant neuropathological markers assessed, most likely because the AD transgenic mice were evaluated at a disease stage too early to detect significant pathological changes. Thus, the underlying mechanisms for CBD’s effect on social recognition memory require further investigation. Full article

Wireless Sensor and Actor Networks (WSANs) are critical for industrial automation in the context of Industry 4.0, yet the optimal placement of actors to ensure connectivity and coverage remains an NP-hard problem. This study addresses the Actor Placement Problem (APP) in constrained, two-zone industrial environments. We propose a hybrid system, the PSO-HC-DGA hybrid system, which integrates Particle Swarm Optimization (PSO), Hill Climbing (HC), and the Distributed Genetic Algorithm (DGA). We evaluate four crossover methods (UNDX, SPX, BLX-$\alpha$, and psBLX) combined with two actor replacement methods (RIWM and FC-RDVM) for small-, medium-, and large-scale scenarios. The simulation results demonstrate that psBLX is the most effective of the four crossover methods. In the small-scale scenario, it achieved better load balancing combined with RIWM, while in the medium-scale scenario, psBLX achieved full sensor coverage with RIWM and good load balancing with FC-RDVM. For the large-scale scenario, we compared the performance of the implemented hybrid system with that of a PSO system. The hybrid system showed 100% connectivity and achieved better sensor coverage than the PSO system. The Kruskal–Wallis test confirmed that the performance differences in load balancing were statistically significant. We conclude that the proposed hybrid system using psBLX enables robust and high-performance deployment in two-zone industrial WSANs. Full article

Luteolin (Ltn), a natural flavonoid, effectively inhibits microglial activation in Alzheimer’s disease (AD) with promising therapeutic potential, but its efficacy is severely limited by the blood–brain barrier (BBB). To overcome this obstacle, this study prepared poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs)—designated as TGN/RAP12-RBC-NPs@Ltn—which were coated with red blood cell membranes (RBCm) functionalized with two peptides, TGN (TGNYKALHPHN) and RAP12 (EAKIEKHNHYQK). The results demonstrated that TGN significantly enhanced BBB permeability, while RAP12 enabled effective targeting and delivery of TGN/RAP12-RBC-NPs@Ltn to microglial mitochondria in the brain. In addition, the presence of RBCm significantly inhibited the phagocytosis of NPs by macrophages, exerting a notable role in immune evasion. Meanwhile, the study confirmed that encapsulating Ltn within NPs significantly enhanced cognitive function in APP/PS1 mice, modulated the expression of key mitochondrial metabolic enzymes—pyruvate dehydrogenase (PDH) and its phosphorylated forms (pS232PDH, pS293PDH, pS300PDH)—in microglia, thereby ameliorating mitochondrial dysfunction and effectively regulating the neuroinflammatory environment in the mouse brain, and ultimately contributed to therapeutic efficacy. From this, it could be seen that TGN/RAP12-RBC-NPs@Ltn could significantly enhance the therapeutic effect of Ltn on AD, providing an effective treatment strategy for delaying the progression of AD. Full article

Alzheimer’s disease (AD) is marked by amyloid plaques, hyperphosphorylated TAU proteins, and neuroinflammation. The APP/PS1 mouse model is widely used to study AD pathogenesis. In this study, we investigated the expression of chemokines and their receptors, which may play a role in AD’s pathological mechanisms, using brain cortex tissue from female APP/PS1 mice aged 20–21 months. We analyzed several chemokine receptors (CCR1, CCR2, CCR3, CCR4, CCR6, CCR7, CCR9, and CCR10) by Western blot and focused on CCR6, CCR7, and CCR10 using RT-PCR. Additionally, we quantified the levels of chemokines (CCL6, CCL8, CCL19, CCL20, CCL24, and CCL27) by RT-PCR. Our results showed a significant decrease in CCL8 and CCL19, along with their respective receptors, in the APP/PS1 mice compared to controls. On the other hand, we observed a notable increase in CCL6, CCL24, CCL20, CCL27, and their receptors. Chemokines like CCL8 and CCL20, involved in inflammatory responses, may reveal how neuroinflammation contributes to AD. CCL19 and CCL27 are linked to immune cell trafficking, which may help explain immune cell interactions with amyloid plaques and TAU tangles in the CNS. Overall, the altered expression of chemokines such as CCL24 could serve as biomarkers for early AD detection and monitoring disease progression. These findings suggest potential therapeutic targets to modulate immune responses and reduce neuroinflammation in AD. Full article

Aging and Alzheimer’s disease (AD) are associated with profound changes in glial cell morphology and signaling. This study investigates the three-dimensional morphology of microglia and the intracellular localization of phosphorylated SMAD proteins as downstream effectors of transforming growth factor β (TGF-β) signaling in the amyloid precursor protein and presenilin-1 (APP/PS1) transgenic mouse model of Alzheimer’s disease. Using confocal microscopy and Simple Neurite Tracer software, we reconstructed and quantitatively analyzed glial cell morphology in aged wild-type and APP/PS1 mice. Immunofluorescence staining revealed altered pSMAD2 distribution in microglia, suggesting impaired canonical TGF-β signaling. Our findings indicate a disturbed glial morphology and dysfunctional TGF-β signaling cascade in the APP/PS1 model, underlining their potential role in Alzheimer’s disease pathogenesis. Full article

Alzheimer’s disease (AD) is regarded as a disease of the brain. Cumulative evidence increasingly supports a full-body view on this disorder, with the liver and kidneys playing an important role in amyloid clearance. The latter is likely potentiated by caloric restriction (CR), whose impact on the metabolism of amyloid-handling tissues is poorly understood. We studied the sex-specific effects of amyloidosis and CR on oxidative and metabolic processes in APPPS1 mice that express amyloidogenic proteins. Wild-type (WT) and APPPS1 mice were either fed ad libitum (AL) or received 70% of their AL caloric intake (CR). Compared to age-matched WT controls, the brain, liver, and kidney of 9-month-old AL APPPS1 mice exhibited higher levels of oxidative stress markers, higher superoxide dismutase, and lower catalase activities. These differences were sex- and tissue-specific, with kidneys showing the largest AD-induced differences between sexes. In addition, APPPS1 mice possessed higher pyruvate kinase activity than WT mice in all organs and higher hexokinase and phosphofructokinase activities in the brain, with stronger effects in males. CR intensified the accumulation of lipid peroxides in the liver and the female brain but decreased it in the female kidney. CR potentiated glycolysis, predominantly in females and modulated glutathione-dependent enzymes, in a sex-dependent manner. Full article