Osmundacetone ameliorates Alzheimer's-like pathologies by inhibiting ß-amyloid fibrillation, oxidative damage and neuroinflammation in APP/PS1 transgenic mice.

BACKGROUND: ß-Amyloid (Aß) fibrillation is critical for Aß deposition and cytotoxicity during the progression of Alzheimer's disease (AD). Consequently, anti-Aß monoclonal antibody drugs targeting Aß oligomers and aggregation are considered potential therapeutic strategies for AD treatment. Similar to the working mechanisms of anti-Aß monoclonal antibody drugs, our study identified osmundacetone (OAC), a small-molecule compound isolated from the traditional Chinese medicine Rhizoma Osmundae, as exerting anti-AD effects by targeting Aß. PURPOSE: This study sought to determine whether OAC influences the Aß burden in APP/PS1 mice and to identify potential regulatory mechanisms. METHODS: Five-month-old APP/PS1 mice were injected intraperitoneally with OAC at a dose of 1 mg/kg for 12 weeks. The cognitive functions of the mice were assessed via the Morris water maze test and the open field test. Osmundacetone was analyzed via molecular docking, an isothermal dose‒response fingerprint-cellular context thermal shift assay, a thioflavine T fluorescence assay, and an atomic force microscopy assay to analyze the effects of OAC on Aß fibrillation. Immunofluorescence, immunoblotting, and immunohistochemistry were used to assess Aß clearance, AD pathology, oxidative stress, and inflammatory responses. RESULTS: The innovative biochemical and physical data illustrated that the ability of OAC to inhibit Aß fibrillation was accomplished by binding directly to Aß, which differed from the majority of previously reported natural polyphenols that modulate the Aß content and structure in an indirect manner. The inhibition of Aß fibrosis by OAC subsequently promoted Aß lysosomal degradation, resulting in a decreased Aß burden in APP/PS1 mice. Furthermore, OAC treatment inhibited oxidative damage by upregulating glutathione peroxidase expression and attenuated the production of inflammatory factors by downregulating nuclear factor-kB phosphorylation in APP/PS1 mice. CONCLUSION: These findings demonstrate, for the first time, that OAC could reduce the brain Aß burden in APP/PS1 mice by inhibiting Aß fibrillation through direct binding to Aß and improve cognitive dysfunction by attenuating oxidative damage and neuroinflammation. These findings indicate that OAC may be a promising candidate for the treatment of AD.

Astrocyte-derived lactoferrin inhibits neuronal ferroptosis by reducing iron content and GPX4 degradation in APP/PS1 transgenic mice.

Increased astrocytic lactoferrin (Lf) expression was observed in the brains of elderly individuals and Alzheimer's disease (AD) patients. Our previous study revealed that astrocytic Lf overexpression improved cognitive capacity by facilitating Lf secretion to neurons to inhibit ß-amyloid protein (Aß) production in APP/PS1 mice. Here, we further discovered that astrocytic Lf overexpression inhibited neuronal loss by decreasing iron accumulation and increasing glutathione peroxidase 4 (GPX4) expression in neurons within APP/PS1 mice. Furthermore, human Lf (hLf) treatment inhibited ammonium ferric citrate (FAC)-induced ferroptosis by chelating intracellular iron. Additionally, machine learning analysis uncovered a correlation between Lf and GPX4. hLf treatment boosted low-density lipoprotein receptor-related protein 1 (LRP1) internalization and facilitated its interaction with heat shock cognate 70 (HSC70), thereby inhibiting HSC70 binds to GPX4, and eventually attenuating GPX4 degradation and FAC-induced ferroptosis. Overall, astrocytic Lf overexpression inhibited neuronal ferroptosis through two pathways: reducing intracellular iron accumulation and promoting GPX4 expression via inhibiting chaperone-mediated autophagy (CMA)-mediated GPX4 degradation. Hence, upregulating astrocytic Lf expression is a promising strategy for combating AD.

Identification of AS1842856 as a novel small-molecule GSK3α/ß inhibitor against Tauopathy by accelerating GSK3α/ß exocytosis.

Glycogen synthase kinase-3α/ß (GSK3α/ß) is a critical kinase for Tau hyperphosphorylation which contributes to neurodegeneration. Despite the termination of clinical trials for GSK3α/ß inhibitors in Alzheimer's disease (AD) treatment, there is a pressing need for novel therapeutic strategies targeting GSK3α/ß. Here, we identified the compound AS1842856 (AS), a specific forkhead box protein O1 (FOXO1) inhibitor, reduced intracellular GSK3α/ß content in a FOXO1-independent manner. Specifically, AS directly bound to GSK3α/ß, promoting its translocation to the multivesicular bodies (MVBs) and accelerating exocytosis, ultimately decreasing intracellular GSK3α/ß content. Expectedly, AS treatment effectively suppressed Tau hyperphosphorylation in cells exposed to okadaic acid or expressing the TauP301S mutant. Furthermore, AS was visualized to penetrate the blood-brain barrier (BBB) using an imaging mass microscope. Long-term treatment of AS enhanced cognitive function in P301S transgenic mice by mitigating Tau hyperphosphorylation through downregulation of GSK3α/ß expression in the brain. Altogether, AS represents a novel small-molecule GSK3α/ß inhibitor that facilitates GSK3α/ß exocytosis, holding promise as a therapeutic agent for GSK3α/ß hyperactivation-associated disorders.

Potential Application Prospects of Biomolecule-Modified Two-Dimensional Chiral Nanomaterials in Biomedicine.

Chirality, one of the most fundamental properties of natural molecules, plays a significant role in biochemical reactions. Nanomaterials with chiral characteristics have superior properties, such as catalytic properties, optoelectronic properties, and photothermal properties, which have significant potential for specific applications in nanomedicine. Biomolecular modifications such as nucleic acids, peptides, proteins, and polysaccharides are sources of chirality for nanomaterials with great potential for application in addition to intrinsic chirality, artificial macromolecules, and metals. Two-dimensional (2D) nanomaterials, as opposed to other dimensions, due to proper surface area, extensive modification sites, drug loading potential, and simplicity of preparation, are prepared and utilized in diagnostic applications, drug delivery research, and tumor therapy. Current advanced studies on 2D chiral nanomaterials for biomedicine are focused on novel chiral development, structural control, and materials sustainability applications. However, despite the advances in biomedical research, chiral 2D nanomaterials still confront challenges such as the difficulty of synthesis, quality control, batch preparation, chiral stability, and chiral recognition and selectivity. This review aims to provide a comprehensive overview of the origins, synthesis, applications, and challenges of 2D chiral nanomaterials with biomolecules as cargo and chiral modifications and highlight their potential roles in biomedicine.

Astrocyte-derived lactoferrin reduces ß-amyloid burden by promoting the interaction between p38 kinase and PP2A phosphatase in male APP/PS1 transgenic mice.

BACKGROUND AND PURPOSE: Overexpression of astrocytic lactoferrin (Lf) was observed in the brain of Alzheimer's disease (AD) patients, whereas the role of astrocytic Lf in AD progression remains unexplored. In this study, we aimed to evaluate the effects of astrocytic Lf on AD progression. EXPERIMENTAL APPROACH: Male APP/PS1 mice with astrocytes overexpressing human Lf were developed to evaluate the effects of astrocytic Lf on AD progression. N2a-sw cells also were employed to further uncover the mechanism of astrocytic Lf on ß-amyloid (Aß) production. KEY RESULTS: Astrocytic Lf overexpression increased protein phosphatase 2A (PP2A) activity and reduced amyloid precursor protein (APP) phosphorylation, Aß burden and tau hyperphosphorylation in APP/PS1 mice. Mechanistically, astrocytic Lf overexpression promoted the uptake of astrocytic Lf into neurons in APP/PS1 mice, and conditional medium from astrocytes overexpressing Lf inhibited p-APP (Thr668) expression in N2a-sw cells. Furthermore, recombinant human Lf (hLf) significantly enhanced PP2A activity and inhibited p-APP expression, whereas inhibition of p38 or PP2A activities abrogated the hLf-induced p-APP down-regulation in N2a-sw cells. Additionally, hLf promoted the interaction of p38 and PP2A via p38 activation, thereby enhancing PP2A activity, and low-density lipoprotein receptor-related protein 1 (LRP1) knockdown significantly reversed the hLf-induced p38 activation and p-APP down-regulation. CONCLUSIONS AND IMPLICATIONS: Our data suggested that astrocytic Lf promoted neuronal p38 activation, via targeting to LRP1, subsequently promoting p38 binding to PP2A to enhance PP2A enzyme activity, which finally inhibited Aß production via APP dephosphorylation. In conclusion, promoting astrocytic Lf expression may be a potential strategy against AD. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

From zinc homeostasis to disease progression: Unveiling the neurodegenerative puzzle.

Zinc is a crucial trace element in the human body, playing a role in various physiological processes such as oxidative stress, neurotransmission, protein synthesis, and DNA repair. The zinc transporters (ZnTs) family members are responsible for exporting intracellular zinc, while Zrt- and Irt-like proteins (ZIPs) are involved in importing extracellular zinc. These processes are essential for maintaining cellular zinc homeostasis. Imbalances in zinc metabolism have been linked to the development of neurodegenerative diseases. Disruptions in zinc levels can impact the survival and activity of neurons, thereby contributing to the progression of neurodegenerative diseases through mechanisms like cell apoptosis regulation, protein phase separation, ferroptosis, oxidative stress, and neuroinflammation. Therefore, conducting a systematic review of the regulatory network of zinc and investigating the relationship between zinc dysmetabolism and neurodegenerative diseases can enhance our understanding of the pathogenesis of these diseases. Additionally, it may offer new insights and approaches for the treatment of neurodegenerative diseases.

Graphdiyne nanoplatforms for photothermal-ferroptosis combination therapy against glioblastoma.

Glioblastoma (GBM) is one of the most malignant tumors of the central nervous system and has a poor prognosis. GBM cells are highly sensitive to ferroptosis and heat, suggesting thermotherapy-ferroptosis as a new strategy for GBM treatment. With its biocompatibility and photothermal conversion efficiency, graphdiyne (GDY) has become a high-profile nanomaterial. Here, the ferroptosis inducer FIN56 was employed to construct GDY-FIN56-RAP (GFR) polymer self-assembled nanoplatforms against GBM. GDY could effectively load FIN56 and FIN56 released from GFR in a pH-dependent manner. The GFR nanoplatforms possessed the advantages of penetrating the BBB and acidic environment-induced in situ FIN56 release. Moreover, GFR nanoplatforms induced GBM cell ferroptosis by inhibiting GPX4 expression, and 808 nm irradiation reinforced GFR-mediated ferroptosis by elevating the temperature and promoting FIN56 release from GFR. In addition, the GFR nanoplatforms were inclined to locate in tumor tissue, inhibit GBM growth, and prolong lifespan by inducing GPX4-mediated ferroptosis in an orthotopic xenograft mouse model of GBM; meanwhile, 808 nm irradiation further improved these GFR-mediated effects. Hence, GFR may be a potential nanomedicine for cancer therapy, and GFR combined with photothermal therapy may be a promising strategy against GBM.

Telomerase reverse transcriptase and neurodegenerative diseases.

Neurodegenerative diseases (NDs) are chronic conditions that result in progressive damage to the nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Age is a major risk factor for NDs. Telomere shortening is a biological marker of cellular aging, and telomerase reverse transcriptase (TERT) has been shown to slow down this process by maintaining telomere length. The blood-brain barrier (BBB) makes the brain a unique immune organ, and while the number of T cells present in the central nervous system is limited, they play an important role in NDs. Research suggests that NDs can be influenced by modulating peripheral T cell immune responses, and that TERT may play a significant role in T cell senescence and NDs. This review focuses on the current state of research on TERT in NDs and explores the potential connections between TERT, T cells, and NDs. Further studies on aging and telomeres may provide valuable insights for developing therapeutic strategies for age-related diseases.

T cell aging and Alzheimer's disease.

The brain has long been considered an immune-privileged organ due to the presence of the blood-brain barrier (BBB). However, recent discoveries have revealed the underestimated role of T cells in the brain through the meningeal lymphatic system. Age is the primary risk factor for Alzheimer's disease (AD), resulting in marked age-dependent changes in T cells. Manipulating peripheral T cell immune response has been shown to impact AD, but the relationship between T cell aging and AD remains poorly understood. Given the limited success of targeting amyloid beta (Aß) and the growing evidence of T cells' involvement in non-lymphoid organ aging, a deeper understanding of the relationship between T cells and AD in the context of aging is crucial for advancing therapeutic progress. In this review, we comprehensively examine existing studies on T cells and AD and offer an integrated perspective on their interconnections in the context of aging. This understanding can inform the development of new interventions to prevent or treat AD.

How the use of an online healthcare community affects the doctor-patient relationship: An empirical study in China.

Possible improvements to the doctor-patient relationship are an important subject confronting national healthcare policy and health institutions. In recent years, online healthcare communities have changed the ways in which doctors and patients communicate, especially during the COVID-19 pandemic. However, previous research on how usage of online healthcare communities has affected the doctor-patient relationship is rather limited. This paper proposes a research model to investigate the relationship between online healthcare community usage and the doctor-patient relationship. An analysis of 313 patients' data using structural equation modeling showed the following. First, the use of an online healthcare community has a positive impact on doctor-patient communication, helps improve the performance of healthcare procedures, and reduces healthcare costs. Second, doctor-patient communication and healthcare costs have a positive impact on patients' emotional dependence and patients' perception of healthcare quality, while healthcare procedures do not have this impact. Finally, patients' emotional dependence and perception of healthcare quality have a positive effect on doctor-patient relationship through the mediator of patients' satisfaction.

The metal ion hypothesis of Alzheimer's disease and the anti-neuroinflammatory effect of metal chelators.

Alzheimer's disease (AD), characterized by the ß-amyloid protein (Aß) deposition and tau hyperphosphorylation, is the most common dementia with uncertain etiology. The clinical trials of Aß monoclonal antibody drugs have almost failed, giving rise to great attention on the other etiologic hypothesis regarding AD such as metal ions dysmetabolism and chronic neuroinflammation. Mounting evidence revealed that the metal ions (iron, copper, and zinc) were dysregulated in the susceptible brain regions of AD patients, which was highly associated with Aß deposition, tau hyperphosphorylation, neuronal loss, as well as neuroinflammation. Further studies uncovered that iron, copper and zinc could not only enhance the production of Aß but also directly bind to Aß and tau to promote their aggregations. In addition, the accumulation of iron and copper could respectively promote ferroptosis and cuproptosis. Therefore, the metal ion chelators were recognized as promising agents for treating AD. This review comprehensively summarized the effects of metal ions on the Aß dynamics and tau phosphorylation in the progression of AD. Furthermore, taking chronic neuroinflammation contributes to the progression of AD, we also provided a summary of the mechanisms concerning metal ions on neuroinflammation and highlighted the metal ion chelators may be potential agents to alleviate neuroinflammation under the condition of AD. Nevertheless, more investigations regarding metal ions on neuroinflammation should be taken into practice, and the effects of metal ion chelators on neuroinflammation should gain more attention. Running title: Metal chelators against neuroinflammation.

Energy Crisis Links to Autophagy and Ferroptosis in Alzheimer's Disease: Current Evidence and Future Avenues.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), and AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, which play important roles in regulating beta-amyloid (Aß) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD and discussed the interplays existing between energy crisis, autophagy, and ferroptosis. In addition, we highlighted the potential network in which autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new insight into developing strategies for treating AD; meanwhile, the energy crisis in the progression of AD should gain more attention.

Antecedents and Consequences of Online Healthcare Community Usage: A Grounded Theory Approach.

The online healthcare community has grown rapidly in recent years. However, the antecedents and consequences of the use of online healthcare community platforms have not been systematized. Using grounded theory, this study collects first-hand data on the use of online healthcare communities through in-depth interviews and analyzes the interview data using a three-level coding approach including open coding, axial coding, and selective coding. The results showed the following. (1) Doctors, hospitals, and the online platforms themselves, along with the impact of healthcare environmental factors, affect patients using the online healthcare community. (2) The use of an online healthcare platform affects patient-related factors, such as emotional dependence and patient satisfaction, as well as factors related to doctor-patient interactions, such as the perception of healthcare quality and the doctor-patient relationship, through mediating factors, including doctor-patient communication, treatment processes, and healthcare costs. (3) Improving patients' healthcare experience and the doctor-patient relationship may feed back into operation quality and the operating environment of the online healthcare community, thus promoting the promotion and use of an online healthcare community platform.

Astrocyte-specific loss of lactoferrin influences neuronal structure and function by interfering with cholesterol synthesis.

Growing evidence indicates that circulating lactoferrin (Lf) is implicated in peripheral cholesterol metabolism disorders. It has emerged that the distribution of Lf changes in astrocytes of aging brains and those exhibiting neurodegeneration; however, its physiological and/or pathological role remains unknown. Here, we demonstrate that astrocyte-specific knockout of Lf (designated cKO) led to decreased body weight and cognitive abnormalities during early life in mice. Accordingly, there was a reduction in neuronal outgrowth and synaptic structure in cKO mice. Importantly, Lf deficiency in the primary astrocytes led to decreased sterol regulatory element binding protein 2 (Srebp2) activation and cholesterol production, and cholesterol content in cKO mice and/or in astrocytes was restored by exogenous Lf or a Srebp2 agonist. Moreover, neuronal dendritic complexity and total dendritic length were decreased after culture with the culture medium of the primary astrocytes derived from cKO mice and that this decrease was reversed after cholesterol supplementation. Alternatively, these alterations were associated with an activation of AMP-activated protein kinase (AMPK) and inhibition of SREBP2 nuclear translocation. These data suggest that astrocytic Lf might directly or indirectly control in situ cholesterol synthesis, which may be implicated in neurodevelopment and several neurological diseases.

Inhibition of SIRT2 promotes APP acetylation and ameliorates cognitive impairment in APP/PS1 transgenic mice.

Aging is a primary risk factor for neurodegenerative diseases, such as Alzheimer's disease (AD). SIRT2, an NAD+(nicotinamide adenine dinucleotide)-dependent deacetylase, accumulates in the aging brain. Here, we report that, in the amyloid precursor protein (APP)/PS1 transgenic mouse model of AD, genetic deletion of SIRT2 or pharmacological inhibition of SIRT2 ameliorates cognitive impairment. We find that suppression of SIRT2 enhances acetylation of APP, which promotes non-amyloidogenic processing of APP at the cell surface, leading to increased soluble APP-α (sAPPα). We discover that lysines 132 and 134 of the major pathogenic protein ß-amyloid (Aß) precursor are acetylated and that these residues are deacetylated by SIRT2. Strikingly, exogenous expression of wild-type or an acetylation-mimic APP mutant protects cultured primary neurons from Aß42 challenge. Our study identifies SIRT2-mediated deacetylation of APP on K132 and K134 as a regulated post-translational modification (PTM) and suggests inhibition of SIRT2 as a potential therapeutic strategy for AD.

How to Maintain a Sustainable Doctor-Patient Relationship in Healthcare in China: A Structural Equation Modeling Approach.

It is important to identify means of improving and maintaining a sustainable doctor-patient relationship to address current healthcare issues. Although many studies have made outstanding contributions to the healthcare doctor-patient relationship literature, little work has been done to explore the influencing elements of the doctor-patient relationship in relation to expectation confirmation theory. To fill this gap, this study produced a theoretical framework model of the influencing factors of the doctor-patient relationship according to the expectation confirmation theory. Data from 335 Chinese patients were analyzed using a structural equation modeling method, and the results showed that patient satisfaction and patient trust are the most important factors in building a good relationship between doctor and patient. Furthermore, three components of postdiagnosis patient's perception, namely, perceived service quality, perceived communication quality, and perceived service attitude, are examined. These have a significant impact on patient confirmation. These three components ultimately affect the doctor-patient relationship. This study will be helpful for doctors to understand patients' service demands and their future diagnosis behavior. The proposals of this study may lead to optimization of the process of diagnosis and improvements in the quality of clinic services.

Effect of Fufang Huangqi Decoction on the Gut Microbiota in Patients With Class I or II Myasthenia Gravis.

Objective: To investigate the effect of Fufang Huangqi Decoction on the gut microbiota in patients with class I or II myasthenia gravis (MG) and to explore the correlation between gut microbiota and MG (registration number, ChiCTR2100048367; registration website, http://www.chictr.org.cn/listbycreater.aspx; NCBI: SRP338707). Methods: In this study, microbial community composition and diversity analyses were carried out on fecal specimens from MG patients who did not take Fufang Huangqi Decoction (control group, n = 8) and those who took Fufang Huangqi Decoction and achieved remarkable alleviation of symptoms (medication group, n = 8). The abundance, diversity within and between habitats, taxonomic differences and corresponding discrimination markers of gut microbiota in the control group and medicated group were assessed. Results: Compared with the control group, the medicated group showed a significantly decreased abundance of Bacteroidetes (P < 0.05) and significantly increased abundance of Actinobacteria at the phylum level, a significantly decreased abundance of Bacteroidaceae (P < 0.05) and significantly increased abundance of Bifidobacteriaceae at the family level and a significantly decreased abundance of Blautia and Bacteroides (P < 0.05) and significantly increased abundance of Bifidobacterium, Lactobacillus and Roseburia at the genus level. Compared to the control group, the medicated group had decreased abundance, diversity, and genetic diversity of the communities and increased coverage, but the differences were not significant (P > 0.05); the markers that differed significantly between communities at the genus level and influenced the differences between groups were Blautia, Bacteroides, Bifidobacterium and Lactobacillus. Conclusions: MG patients have obvious gut microbiota-associated metabolic disorders. Fufang Huangqi Decoction regulates the gut microbiota in patients with class I or II MG by reducing the abundance of Blautia and Bacteroides and increasing the abundance of Bifidobacterium and Lactobacillus. The correlation between gut microbiota and MG may be related to cell-mediated immunity.

Identification and Spatial Visualization of Dysregulated Bile Acid Metabolism in High-Fat Diet-Fed Mice by Mass Spectral Imaging.

Changes in overall bile acid (BA) levels and specific BA metabolites are involved in metabolic diseases, gastrointestinal, and liver cancer. BAs have become established as important signaling molecules that enable fine-tuned inter-tissue communication within the enterohepatic circulation. The liver, BAs site of production, displayed physiological and functional zonal differences in the periportal zone versus the centrilobular zone. In addition, BA metabolism shows regional differences in the intestinal tract. However, there is no available method to detect the spatial distribution and molecular profiling of BAs within the enterohepatic circulation. Herein, we demonstrated the application in mass spectrometry imaging (MSI) with a high spatial resolution (3 µm) plus mass accuracy matrix-assisted laser desorption ionization (MALDI) to imaging BAs and N-1-naphthylphthalamic acid (NPA). Our results could clearly determine the zonation patterns and regional difference characteristics of BAs on mouse liver, ileum, and colon tissue sections, and the relative content of BAs based on NPA could also be ascertained. In conclusion, our method promoted the accessibility of spatial localization and quantitative study of BAs on gastrointestinal tissue sections and demonstrated that MALDI-MSI was a valuable tool to investigate and locate several BA molecules in different tissue types leading to a better understanding of the role of BAs behind the gastrointestinal diseases.

Kai-Xin-San Inhibits Tau Pathology and Neuronal Apoptosis in Aged SAMP8 Mice.

Alzheimer's disease (AD) is an age-related neurological disorder. Currently, there is no effective cure for AD due to its complexity in pathogenesis. In light of the complex pathogenesis of AD, the traditional Chinese medicine (TCM) formula Kai-Xin-San (KXS), which was used for amnesia treatment, has been proved to improve cognitive function in AD animal models. However, the active ingredients and the mechanism of KXS have not yet been clearly elucidated. In this study, network pharmacology analysis predicts that KXS yields 168 candidate compounds acting on 863 potential targets, 30 of which are associated with AD. Enrichment analysis revealed that the therapeutic mechanisms of KXS for AD are associated with the inhibition of Tau protein hyperphosphorylation, inflammation, and apoptosis. Therefore, we chose 7-month-old senescence-accelerated mouse prone 8 (SAMP8) mice as AD mouse model, which harbors the behavioral and pathological hallmarks of AD. Subsequently, the potential underlying action mechanisms of KXS on AD predicted by the network pharmacology analyses were experimentally validated in SAMP8 mice after intragastric administration of KXS for 3 months. We observed that KXS upregulated AKT phosphorylation, suppressed GSK3ß and CDK5 activation, and inhibited the TLR4/MyD88/NF-κB signaling pathway to attenuate Tau hyperphosphorylation and neuroinflammation, thus suppressing neuronal apoptosis and improving the cognitive impairment of aged SAMP8 mice. Taken together, our findings reveal a multi-component and multi-target therapeutic mechanism of KXS for attenuating the progression of AD, contributing to the future development of TCM modernization, including KXS, and broader clinical application.