Search Results (631)

In familial Alzheimer’s disease (FAD), presenilin 1 (PSEN1) E280A cholinergic-like neurons (ChLNs) induce aberrant secretion of extracellular amyloid beta (eAβ). How PSEN1 E280A ChLNs-eAβ affects microglial activity is still unknown. We obtained induced microglia-like cells (iMG) from human peripheral blood cells (hPBCs) in a 15-day differentiation process to investigate the effect of bolus addition of Aβ42, PSEN1 E280A cholinergic-like neuron (ChLN)-derived culture supernatants, and PSEN1 E280A ChLNs on wild type (WT) iMG, PSEN1 E280A iMG, and sporadic Alzheimer’s disease (SAD) iMG. We found that WT iMG cells, when challenged with non-cellular (e.g., lipopolysaccharide, LPS) or cellular (e.g., Aβ42, PSEN1 E280A ChLN-derived culture supernatants) microenvironments, closely resemble primary human microglia in terms of morphology (resembling an “amoeboid-like phenotype”), expression of surface markers (Ionized calcium-binding adapter molecule 1, IBA-1; transmembrane protein 119, TMEM119), phagocytic ability (high pHrodo™ Red E. coli BioParticles™ phagocytic activity), immune metabolism (i.e., high generation of reactive oxygen species, ROS), increase in mitochondrial membrane potential (ΔΨm), response to ATP-induced transient intracellular Ca²⁺ influx, cell polarization (cluster of differentiation 68 (CD68)/CD206 ratio: M1 phenotype), cell migration activity according to the scratch wound assay, and especially in their inflammatory response (secretion of cytokine interleukin-6, IL-6; Tumor necrosis factor alpha, TNF-α). We also found that PSEN1 E280A and SAD iMG are physiologically unresponsive to ATP-induced Ca²⁺ influx, have reduced phagocytic activity, and diminished expression of Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) protein, but when co-cultured with PSEN1 E280A ChLNs, iMG shows an increase in pro-inflammatory phenotype (M1) and secretes high levels of cytokines IL-6 and TNF-α. As a result, PSEN1 E280A and SAD iMG induce apoptosis in PSEN1 E280A ChLNs as evidenced by abnormal phosphorylation of protein TAU at residue T205 and cleaved caspase 3 (CC3). Taken together, these results suggest that PSEN1 E280A ChLNs initiate a vicious cycle between damaged neurons and M1 phenotype microglia, resulting in excessive ChLN death. Our findings provide a suitable platform for the exploration of novel therapeutic approaches for the fight against FAD. Full article

Background and Objectives: Alzheimer’s disease (AD) has become a serious health problem. Agomelatine (Ago) is a neuroprotective antidepressant. This study aimed to assess how Ago influences behavioral outcomes in AD-like rat model. Materials and Methods: Forty-eight Wistar albino rats were allocated into four groups: Control (C), Alzheimer’s disease-like model (AD), Alzheimer’s disease-like model treated with Ago (ADAgo), and Ago alone (Ago). Physiological saline was injected intrahippocampally in C and Ago animals, whereas Aβ peptide was delivered similarly in AD and ADAgo rats. On day 15, 0.9% NaCl was administered to the C and AD groups, and Agomelatine (1 mg/kg/day) was infused into ADAgo and Ago rats via osmotic pumps for 30 days. Behavioral functions were evaluated using Open Field (OF), Forced Swim (FST), and Morris Water Maze (MWM) tests. Brain tissues were examined histopathologically. Neuritin, Nestin, DCX, NeuN, BDNF, MASH1, MT1, and MT2 transcripts were quantified by real-time PCR. Statistical analyses were performed in R 4.3.1, with p < 0.05 deemed significant. Results: In the FST, swimming, climbing, immobility time, and mobility percentage differed significantly among groups (p < 0.05). In the MWM, AD rats exhibited impaired learning and memory that was ameliorated by Ago treatment (p < 0.05). DCX expression decreased in AD rats but was elevated by Ago (p < 0.05). Nestin levels differed significantly between control and AD animals; MT1 expression varied between control and AD cohorts; and MT2 transcript levels were significantly lower in AD, ADAgo, and Ago groups compared to C (all p < 0.05). Conclusions: Ago exhibits antidepressant-like activity in this experimental AD model and may enhance cognitive function via mechanisms beyond synaptic plasticity and neurogenesis. Full article

Alzheimer’s disease (AD) is a neurodegenerative condition in which amyloid-beta (Aβ) plaques trigger oxidative stress (OS) and neuroinflammation, causing memory loss. OS and neurodegeneration can also be caused by reactive astrocytes, thereby promoting AD via toxic metabolite accumulation in the astrocytic urea cycle. However, the effect of molecular hydrogen (H₂) on this cycle remains unknown. Therefore, we investigated whether H₂ treatment could reduce OS-induced neurodegeneration and memory loss. 5xFAD (n = 14) and wild-type (n = 15) mice were randomized into four groups and treated with either 3% hydrogen gas (H₂) or vehicle for 60 days. Cognitive behaviors were evaluated using the Morris water maze and Y-maze tests. In addition, we used biochemical assays to measure ammonia and hydrogen peroxide (H₂O₂) levels in the hippocampi of the mice and AβO-treated primary mouse astrocytes. Aβ, γ-aminobutyric acid (GABA), and the expression of inflammatory markers were evaluated using immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR). We observed that H₂ treatment significantly prevented cognitive deficits, oxidative stress, the accumulation of toxic metabolites, and the increase in inflammatory markers in 5xFAD mice. These results suggest that H₂ therapy can mitigate toxic metabolites in the astrocytic urea cycle, thereby reducing neurodegeneration and memory loss in AD. Full article

Alzheimer’s disease (AD) is associated with an abnormal accumulation of amyloid β (Aβ) fibrils in the brain parenchyma and cerebrovasculature, which leads to cognitive impairment and cerebrovascular dysfunction. Cerebrovascular endothelial cells play a crucial role in regulating cerebral blood flow, vascular permeability, and neurovascular function. Reactive oxygen species (ROS), particularly those generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), contribute to vascular dysfunction and amyloid deposition in the Alzheimer’s disease (AD) brain. However, the role of the NOX4 isoform in AD pathogenesis remains to be examined. In the present study, we found that NOX4 among the NOX isoforms is predominantly expressed in bEnd.3 mouse brain endothelial cells. Treatment with Aβ₄₀ significantly enhanced the release of H₂O₂ and NO, and increased the endothelial cell viability. To test the involvement of NOX4 in Aβ₄₀-induced H₂O₂ production, we utilized pharmacological inhibitors of NOX isoforms. Aβ₄₀-induced H₂O₂ production was attenuated in the presence of the pan-NOX inhibitor, apocynin, or the NOX1/4-selective inhibitors, setanaxib and GKT136901. Since only the NOX4 isoform is expressed in bEnd.3 cells, these results indicate that NOX4 is responsible for the release of H₂O₂ stimulated by Aβ₄₀. Taken together, the present study demonstrated that Aβ₄₀ peptide exerts beneficial effects in bEnd.3 endothelial cells via the NOX4-dependent mechanism. Full article

Fullerenes and fullerenols exhibit antioxidant and anti-inflammatory properties, making them promising candidates for Alzheimer’s disease (AD) therapy. Unlike conventional anti-inflammatory drugs, these compounds have multitargeted effects, including their ability to inhibit amyloid fibril formation. However, few studies have explored their efficacy in high-validity AD models. Female APPswe/PS1E9 (APP/PS1) mice and their wild-type (WT) littermates were orally administered with fullerene C₆₀ (0.1 mg/kg/day) or fullerenol C₆₀(OH)₂₄ (0.15 mg/kg/day) for 10 months starting at 2 months of age. Behavioral assessments were performed at 12 months of age. Amyloid plaque density and size were analyzed in the brain regions using Congo red staining. The expression of genes related to inflammation and plasticity was examined, and an in vitro assay was used to test the toxicity of fullerenol and its effect on amyloid β peptide 42 (Aβ42)-induced reactive oxygen species (ROS) production. Fullerenol reduced the maximum plaque size in the cortex and hippocampus, decreased the small plaque density in the hippocampus and thalamus, and prevented an increase in glial fibrillary acidic protein (GFAP) positive cell density in the mutants. Both treatments improved cognitive and emotional behaviors and reduced Il1β and increased Sirt1 expression. In vitro, fullerenol was non-toxic across a range of concentrations and reduced Aβ42-induced ROS production in brain endothelial cells and astrocytes. Long-term administration of fullerene or fullerenol improved behavioral and molecular markers of AD in APP/PS1 mice, with fullerenol showing additional benefits in reducing amyloid burden. Full article

Alzheimer’s disease (AD), the most prevalent form of neurodegenerative dementia, is characterized by progressive cognitive decline and neuronal loss. Despite advances in pharmacological treatments, current therapies remain limited in efficacy and often induce adverse effects. Increasing evidence highlights oxidative stress, mitochondrial dysfunction, and disrupted neurotrophic signaling as key contributors to AD pathogenesis. Pulsed electromagnetic fields (PEMFs) are emerging as a non-invasive, multifactorial approach with promising biological effects. In this study, we investigated the neuroprotective potential of PEMFs in NGF-differentiated PC12 cells exposed to hydrogen peroxide (H₂O₂) or amyloid-β peptide (Aβ), both of which model pathological features of AD. PEMF treatment significantly counteracted H₂O₂- and Aβ-induced cytotoxicity by restoring cell viability, reducing reactive oxygen species production, and improving catalase activity. Furthermore, PEMFs preserved the mitochondrial membrane potential and decreased caspase-3 activation and chromatin condensation. Mechanistically, PEMFs inhibited ERK phosphorylation and enhanced cAMP levels, CREB phosphorylation, and BDNF expression, pathways known to support neuronal survival and plasticity. In conclusion, these findings suggest that PEMFs modulate multiple stress response systems, promoting neuroprotection under oxidative and amyloidogenic conditions. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with an unclear etiology. Multiple factors, including oxidative stress and the accumulation of amyloid beta (Aβ) protein in the brain, contribute to neuronal damage. This study investigated Aβ-induced oxidative stress and cellular damage in SH-SY5Y cells, as well as the neuroprotective potential of Indian trumpet tree seed extract (ITS). SH-SY5Y cells were co-treated with Aβ_(25–35) (20 µM) and ITS extract at concentrations of 25 and 50 µg/mL. Cell viability, reactive oxygen species (ROS), malondialdehyde (MDA) levels, and the enzymatic activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were assessed. The expression levels of B-cell lymphoma 2 (Bcl-2) and caspase-3, along with the phosphorylation levels of protein kinase B (Akt), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and cAMP response element-binding protein (CREB), were also evaluated. ITS extract at concentrations of 25 and 50 µg/mL significantly improved SH-SY5Y cell viability following Aβ-induced damage; reduced ROS and MDA levels; and enhanced CAT, SOD, and GSH-Px activities. In addition to upregulating Bcl-2 expression, ITS downregulated caspase-3 expression and increased the phosphorylation of Akt, ERK1/2, and CREB. High-performance liquid chromatography (HPLC) analysis identified baicalin, baicalein, and chrysin as major phenolic compounds in ITS extract. In conclusion, ITS extract attenuated Aβ-induced oxidative stress, enhanced antioxidant defenses and cell viability, suppressed apoptotic signaling, and activated key neuroprotective pathways. These findings provide new insights into the neuroprotective potential of ITS extract; however, further in vivo studies are needed to validate its clinical applicability. Full article

Background/Objectives: To study the efficacy and pharmacological mechanism of the dual-target liposome complex AD808 in the treatment of Alzheimer’s disease. Methods: Using APP/PS1 mouse models, the therapeutic efficacy and pharmacological mechanism of AD808 on Alzheimer’s disease were studied through water maze tests, brain tissue staining, immunofluorescence, and ELISA for inflammatory and neurotrophic factors. Results: AD808 exhibited significant pharmacodynamic effects in improving behavioral and cognitive abilities (70% reduction in escape latency) and repairing damaged nerve cells (90% reduction in Aβ plaque) in Alzheimer’s disease mice. The efficacy of the liposome complex AD808 was significantly better than that of ST707 or gh625-Zn₇MT3 alone. AD808 significantly reduced brain inflammation (57.3% and 61.5% reductions in TNF-α and IL-1β, respectively) in AD (Alzheimer’s disease) mouse models and promoted the upregulation of neurotrophic factors and nerve growth factors (142.8% increase in BDNF, 275.9% in GDNF, and 111.3% in NGF-1) in brain homogenates. By activating the PI3K/AKT signaling pathway in brain microglia, AD808 upregulated TREM2 protein expression and removed Aβ amyloid plaques in the brain. Additionally, it promoted the transition of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, regulated the M1/M2 balance, released anti-inflammatory and neurotrophic factors, reduced chronic inflammation, and enhanced neurological repair. Based on these results, the potential pharmacological mechanism of AD808 against Alzheimer’s disease was proposed. Conclusions: As a dual-target liposome complex, AD808 has shown promising therapeutic potential in the treatment of Alzheimer’s disease, providing a new strategy for innovative drug development. Full article

Cholinergic projections from the basal forebrain to the cortex and hippocampus play a critical role in cognitive functions, many of which rely on signaling through the alpha7 nicotinic acetylcholine receptor (α7nAChR). The Alzheimer’s disease (AD) brain is characterized by the profound impairment of the basal forebrain cholinergic system, including alterations in the levels of α7nAChR in various brain areas. In addition, α7nAChR binds with high affinity to beta amyloid (Aβ), suggesting α7nAChR might mediate some of Aβ’s effects in the brain. Under normal physiological conditions, the interaction between Aβ and α7nAChR appears to be beneficial, supporting normal neurotransmission, synaptic plasticity, and memory functions. However, when levels of Aβ are pathologically elevated, their interaction leads to deleterious effects, implicating α7nAChR in the pathophysiology of AD. In addition to expression in neurons, α7nAChR is expressed in astrocytes and microglia, where it serves as a key component of a cholinergic pathway that regulates neuroinflammation. This review article will cover the role of α7nAChR in neurons, astrocytes and microglia under normal conditions, summarize changes in the expression or function of α7nAChR in neurons and glia in the AD brain, and discuss cell-type specific contributions of α7nAChR to AD pathology with an emphasis on interactions of α7nAChR with Aβ. Full article

Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. In addition to its two major pathological hallmarks, extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), recent evidence highlights the critical roles of mitochondrial dysfunction and neuroinflammation in disease progression. Aβ impairs mitochondrial function, which, in part, can subsequently trigger inflammatory cascades, creating a vicious cycle of neuronal damage. Estrogen receptors (ERs) are widely expressed throughout the brain, and the sex hormone 17β-estradiol (E2) exerts neuroprotection through both anti-inflammatory and mitochondrial mechanisms. While E2 exhibits neuroprotective properties, its mechanisms against Aβ toxicity remain incompletely understood. In this study, we investigated the neuroprotective effects of E2 against Aβ-induced mitochondrial dysfunction and neuroinflammation in primary cortical neurons, with a particular focus on the role of AMP-activated protein kinase (AMPK). We found that E2 treatment significantly increased phosphorylated AMPK and upregulated the expression of mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α), leading to improved mitochondrial respiration. In contrast, Aβ suppressed AMPK and PGC-1α signaling, impaired mitochondrial function, activated the pro-inflammatory nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and reduced neuronal viability. E2 pretreatment also rescued Aβ-induced mitochondrial dysfunction, suppressed NF-κB activation, and, importantly, prevented the decline in neuronal viability. However, the pharmacological inhibition of AMPK using Compound C (CC) abolished these protective effects, resulting in mitochondrial collapse, elevated inflammation, and cell death, highlighting AMPK’s critical role in mediating E2’s actions. Interestingly, while NF-κB inhibition using BAY 11-7082 partially restored mitochondrial respiration, it failed to prevent Aβ-induced cytotoxicity, suggesting that E2’s full neuroprotective effects rely on broader AMPK-dependent mechanisms beyond NF-κB suppression alone. Together, these findings establish AMPK as a key mediator of E2’s protective effects against Aβ-driven mitochondrial dysfunction and neuroinflammation, providing new insights into estrogen-based therapeutic strategies for AD. Full article

This study investigated the potential neuroprotective mechanisms of porcine brain enzyme hydrolysate (PBEH) against Alzheimer’s disease pathology using differentiated SH-SY5Y cells. Differentiated neuronal cells were treated with 40 μM amyloid-β(1-42; Aβ) to induce neurotoxicity, followed by PBEH treatment (12.5–400 μg/mL), Com-A (peptide-based neuroprotective supplement; 200 μg/mL) treatment, and Com-B (herbal extract known for improving memory function; 100 μg/mL) treatment. Key assessments included cell viability, Aβ aggregation in adding 10 μM Aβ, amyloidogenic proteins (APP, BACE), synaptic markers (BDNF, ERK), apoptotic markers (BAX/BCL-2, caspase-3), oxidative stress (reactive oxygen species (ROS)), cholinergic function (ChAT, AChE), MAPK signaling (JNK, p38), and neuroinflammation (IL-1β). PBEH contained high concentrations of amino acids, including L-lysine (32.3 mg/g), L-leucine (42.4 mg/g), L-phenylalanine (30.0 mg/g) and the PSIS peptide (86.9 μg/g). Treatment up to 400 μg/mL showed no cytotoxicity and had cognitive protection effects up to 152% under Aβ stress (p < 0.05). PBEH significantly attenuated Aβ aggregation, decreased APP (28%) and BACE (51%) expression, enhanced synaptic function through increased BDNF, and restored ERK phosphorylation (p < 0.05). Anti-apoptotic effects included a 76% reduction in the BAX/BCL-2 ratio, a 47% decrease in caspase-3, and a 56% reduction in ROS levels. Cholinergic function showed restoration via increased ChAT activity (p < 0.01) and decreased AChE activity (p < 0.05). PBEH reduced IL-1β levels by 70% and suppressed JNK/p38 phosphorylation (p < 0.05). While Com-A enhanced BDNF and Com-B showed anti-inflammatory effects, PBEH demonstrated activity across multiple pathway markers. In conclusion, these findings suggest that PBEH may enable neuronal preservation through multi-pathway modulation, establishing foundational evidence for further mechanistic investigation in cognitive enhancement applications. Full article

Recent advances in cannabinoid-based therapies identified the natural CB2 receptor agonist β-caryophyllene (BCP) as a promising anti-inflammatory and neuroprotective agent. To further explore its therapeutic potential on the management of neurodegenerative disorders, in the present study we investigated the ability of BCP to prevent neuroinflammation and promote neuroprotection by using both in vitro and ex vivo models of β-amyloid induced neurotoxicity. Our data showed that BCP significantly protected human microglial HMC3 cells from Aβ_25-35-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-α, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-κB pathway, which emerged as a central mediator of BCP action. Notably, the use of CB2R- or PPARγ-selective antagonists revealed that the observed NF-κB inhibition by BCP may involve the coordinated activation of both canonical (e.g., CB2R) and non-canonical (e.g., PPARγ) receptors. Moreover, BCP restored the expression of SIRT1, PGC-1α, and BDNF, indicating the involvement of neurotrophic pathways. Clear neuroprotective properties for BCP have been highlighted in Aβ_1-42-treated brain slice preparations, where BCP demonstrated the rescue of both the amyloid-dependent depression of BDNF expression and long-term synaptic potentiation (LTP) impairment. Overall, our results suggest that BCP constitutes an attractive natural molecule for the treatment of Aβ-induced neuroinflammation and synaptic dysfunction, warranting further exploration for its clinical application. Full article

Neuroinflammation, triggered by lipoxygenase (LOX), contributes to Alzheimer’s disease (AD) progression. Overexpression of LOX-5 in patients with AD serum highlights its role. This study assessed the efficacy of the LOX-inhibitor-peptide YWCS in an AD rat model induced by Aβ_25–35 injection. Cognitive tests, magnetic resonance imaging (MRI) scans, and molecular analyses were conducted. YWCS treatment significantly improved cognitive function, as evidenced by improved performance in the open field, novel object recognition, elevated plus maze, and Morris water maze tests. MRI scans revealed hippocampal shrinkage in AD rats and no changes were observed from YWCS treatment. Molecular analysis revealed altered expression of LOX-5, LOX-12, Aβ, γ-secretase components, p-Tau¹⁸¹, Akt, p-Akt, and p53 in AD rats. Immunofluorescence staining confirmed increased expression of LOX, Aβ, and p-Tau¹⁸¹ in the hippocampus of AD rats, which was reduced by YWCS treatment. Serum LOX levels were elevated in AD rats and significantly decreased after YWCS treatment, aligning with previous findings in human AD patients and AD cell models. YWCS offered improvements in behavioral and inflammatory marker regulation and also prevented progression of the disease, as shown by MRI results. These results suggest that YWCS, by targeting LOX, has the potential to be a promising therapeutic agent for AD. Full article

Fish oil’s neuroprotective effects in ethanol-induced liver injury was investigated through the factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) pathway. Male Wistar rats received a control liquid diet (C) or an ethanol diet (E), with 25% or 57% of fat replaced by fish oil (CF25, CF57, EF25, EF57) for 8 weeks. Compared to the C group, the E group exhibited brain damage, including impaired performance of Y maze and novel object recognition test, increased glial fibrillary acidic protein (GFAP)-positive astrocytes, and ionized calcium-binding adapter molecule 1 (Iba-1)-positive microglia. In the prefrontal cortex, glutathione (GSH) and phosphorylated (p)-NRF2 decreased, catalase activity increased, and nqo1 mRNA declined; hippocampal NRF2 and nqo1 were also downregulated. However, compared to the E group, the EF25 and EF57 groups exhibited restored spatial and memory functions, reduced GFAP and Iba-1 expressions, potentiated β-amyloid (Aβ) clearance, and escalated catalase activity. Furthermore, increases in p-NRF2 and elevated hippocampal nqo1 mRNA expressions in the prefrontal cortex were observed in the EF25 and EF57 groups. In conclusion, fish oil ameliorated deficits in spatial and memory functions, and enhanced Aβ1-42 clearance in the prefrontal cortex and hippocampus of rats with chronic ethanol-induced liver damage by activating the NRF2/KEAP1 pathway. Full article

Abnormal deposition of β-amyloid (Aβ) is a core pathological feature of Alzheimer’s disease (AD). Syndecan-3 (SDC3), a type I transmembrane heparan sulfate proteoglycan (HSPG), is abnormally overexpressed in the brains of AD patients and model animals, specifically accumulating in the peri-plaque region of amyloid plaques. However, its regulatory mechanism in the process of Aβ deposition remains unclear. This study aims to clearly define the role of SDC3 in Aβ aggregation and neuroinflammation, two critical processes in AD pathogenesis. Specifically, we investigate how SDC3 modulates Aβ aggregation and its interaction with neuroinflammatory pathways, which may contribute to the progression of AD. By elucidating the mechanisms underlying SDC3’s involvement in these processes, we seek to provide new insights into potential therapeutic targets for AD. In this study, a 5×FAD mouse model with downregulated SDC3 expression was constructed. Behavioral assessments and synaptic function tests were performed to explore the effects of SDC3 on cognition in 5×FAD mice. Immunofluorescence co-localization technology was utilized to analyze the pathological co-deposition of SDC3 and Aβ in the hippocampus, cortex, and meningeal blood vessels. Quantitative assessments of pro-inflammatory cytokines such as Tnf-α and Cxcl10 in the brain were performed through histopathological analysis combined with qPCR. Western blotting was used to examine the phosphorylation status of STAT1/STAT3 and the expression changes of IBA1/GFAP to systematically analyze the molecular mechanisms through which SDC3 regulates AD pathology. This study revealed that SDC3 expression was significantly upregulated in the brain regions of the 5×FAD model mice and co-localized pathologically with Aβ. Cell lineage tracing analysis showed that the elevated SDC3 expression primarily originated from glial cells. Behavioral and pathological results demonstrated that downregulation of SDC3 significantly improved cognitive dysfunction in the model mice and effectively reduced the Aβ burden in the brain. Molecular mechanism studies showed that downregulation of SDC3 reduced the phosphorylation of STAT1 and STAT3, thereby inhibiting the activation of the JAK-STAT and cGAS-STING signaling pathways, reducing the activation of microglia/astrocytes and suppressing the expression of pro-inflammatory cytokines such as Tnf-α and Cxcl10. This study reveals that SDC3 co-localizes with Aβ pathology and synergistically exacerbates neuroinflammation. Knockdown of SDC3 can simultaneously reduce both Aβ deposition and the release of inflammatory factors from glial cells. Mechanistic research indicates that SDC3 drives a “glial activation–cytokine release” vicious cycle through the JAK-STAT and cGAS-STING signaling pathways. These findings suggest that SDC3 may serve as a key hub coordinating amyloid pathology and neuroinflammation in AD, providing new insights for the development of combination therapies targeting the HSPG network. Full article