BACKGROUND:Alzheimer's disease (AD) is a neurodegenerative disorder marked by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles, leading to cognitive decline. Recent research has highlighted the involvement of the gut-brain axis (GBA) in AD progression, suggesting that the disease may also affect the gut. OBJECTIVE:To investigate the transmission of tau from the brain to the gut via the vagus nerve and its impact on gut function, we aimed to develop a novel in vitro system to simulate the GBA. DESIGN:We used an AD animal model to examine the spread of tau from the brain to the colon. We also established an innervated colon-on-a-chip model to replicate the key components of the GBA, including vagal motor neurons, enteric neurons and colon epithelial cells. RESULTS:In ADLPAPT mice, we observed tau aggregates in the nerve plexuses of the colon and confirmed that tau spreads from the hippocampus to the dorsal motor nucleus of the vagus and enteric neurons in the colon. This tau transmission was barely observed in ADLPAPT mice with vagotomy, suggesting the possibility of a neural pathway through which tau pathology can propagate from the brain to the colon. The colon-on-a-chip system effectively mimicked this pathway, showing that tau could be transmitted along the vagal motor neuron to enteric neurons and impact colon epithelium stability. CONCLUSIONS:This study demonstrates that tau pathology can propagate from the brain to the colon via the vagus nerve, providing evidence supporting the brain-to-gut axis in AD.

Alzheimer disease (AD) is a progressive neurodegenerative disorder marked by transcriptomic alterations affecting multiple genes. Many researchers have tried to predict major hallmarks of AD pathogenesis for diagnosis but the association between receptor tyrosine kinase (RTK) pathways and AD diagnosis is still unclear. This study aims to identify RTK-associated gene signatures crucial to AD pathogenesis and assess their potential as diagnostic biomarkers for AD. The study investigated changes in RTK pathway gene expression related to AD by analyzing brain transcriptome data from two independent public data sets (GSE84422 and GSE109887). Differentially expressed genes (DEGs) were analyzed from the GSE84422 and GSE109887 data sets and overlapping genes (oDEGs) were identified. RTK-related genes (ooDEGs) were subsequently selected through functional enrichment analysis. These were further refined into AD-related genes (disease-associated genes (DAGs)) through protein-protein interaction network analysis. Logistic regression and receiver operating characteristic analyses were conducted on the selected DAGs to evaluate their diagnostic potential, with additional gene expression validation performed in brain organoids and primary neurons. A total of 145 genes were identified as oDEGs in the above two data sets, and 18 genes were selected as ooDEGs. Six DAGs (ITGB1, AXL, GFAP, NRG1, CAV1, and RHOA) were selected. The diagnostic powers of the six DAGs for AD were 0.825 (GSE84422) and 0.884 (GSE109887). Human brain organoids and primary neuronal models were used to validate the biological relevance of these findings. AXL and ITGB1 were finally selected as key genes for RTK pathway in AD and were significantly increased in AD.

The gut–brain axis influences neuroinflammation and metabolic homeostasis in Alzheimer’s disease (AD). Disruption of gut microbiota and barrier function promotes amyloid and tau pathology via immune and metabolic dysregulation. In this study, Limosilactobacillus fermentum SRK414 (SRK414) was orally administered to ADLPAPT mice, resulting in reduced Aβ and tau pathology and improved cognition. Multi-omics analysis revealed that SRK414 altered gut microbial composition and increased hippocampal kynurenic acid (KYNA), a metabolite linked to neuroimmune regulation. Increased hippocampal KYNA was associated with metabolic changes consistent with enhanced neuronal fatty acid oxidation, reduced lipid accumulation, and suppressed microglial activation, suggesting improved hippocampal homeostasis. In vitro studies further showed that KYNA attenuated tau-related and inflammatory phenotypes. These findings support a link between gut microbial modulation and brain resilience, and suggest that KYNA may contribute to the neuroprotective effects associated with SRK414 treatment. This study highlights metabolites modulated by SRK414 administration as potential mediators of microbiota-based therapeutic effects in AD.

Noninvasive monitoring of Alzheimer's disease (AD) biomarkers is essential for early diagnosis and treatment efficacy. However, noninvasive monitoring of tau protein secretion, a key biomarker of AD, across developmental stages, age‐related variations, and the interaction between apolipoprotein E ( APOE ) and the tau protein axis is not yet accomplished. Here, the label‐free and non‐invasive detection of multiple tau variants dynamics across developmental stages, age‐related variants, and various APOE isogenic genotyes is presented to investigate the APOE –tau axis using human cerebral organoids (hCOs) combined with surface‐enhanced Raman spectroscopy (SERS). Principal component analysis (PCA) of SERS signals successfully identifies four developmental stages of hCOs: embryonic body, neuronal differentiation, maturation, and maintenance phases. Temporal dynamics of age‐related tau protein secretion are observed, reflecting characteristics associated with AD, which are diminished by astrocyte expression. PCA‐based dimensionality reduction of SERS signals further reveals distinct clustering for different APOE isogenic genotypes, with tau protein secretion increasing from APOE2/E2 to APOE4/E4 , providing direct insight into the APOE –tau axis in AD. This study introduces a novel method for the non‐invasive clinical assessments of disease conditions, dynamics, and the relationship between APOE and tau in AD.

The present study, we investigated the phenolic acid and tanshinone compositions of different cultivars of Salvia miltiorrhiza Bunge grown in Korea and the effects of their ethanolic extracts on inflammation in the cocultures of adipocytes and macrophages. Major phytochemicals in S. miltiorrhiza Bunge were tanshinones (tanshinone IIA and cryptotanshinone) and phenolic acids (salvianolic acid and rosmarinic acid), which were more abundant in the cultivar 'Hongdan' than in other cultivars. The inhibitory effects of the extract of the cultivar 'Hongdan' on nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 macrophages were greater than those of the extracts of the cultivars 'Gosan' and 'Dasan' and those of the commercial product. Treatment with the 'Hongdan' extract exhibited stronger inhibition of lipid accumulation and the expression of major adipogenic transcription factor proteins in adipocytes than that observed in the treatments with the extracts of the other cultivars. Furthermore the 'Hongdan' extract significantly inhibited the secretion of inflammatory mediators, such as interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 in adipocyte and macrophage cocultures. This study suggests that the 'Hongdan' extract has the potential to prevent obesity-related inflammatory diseases.

Rehmannia glutinosa is increasingly recognized as a multifunctional bioresource in health-related industries, including functional foods and cosmetics, driven by its traditional use and rising demand for preventive healthcare. To support its sustainable utilization, numerous cultivars have been developed to improve root yield, bioactive compound content, and adaptability. However, the absence of standardized diagnostic criteria hampers accurate cultivar identification and limits the efficiency of breeding programs. This study examined morphological diversity and conducted genome-wide analyses of Single Nucleotide Polymorphisms (SNPs) and Insertion-Deletion (InDel) variations across nine R. glutinosa cultivars. Twenty-three morphological traits were evaluated, and five traits-primarily related to leaves and seeds-exhibited high discriminatory power (eta(2) > 0.7). Principal component analysis further confirmed that leaf- and seed-specific traits were the most informative for distinguishing cultivars. Whole-genome resequencing revealed substantial genomic variation, with 12.5-16.1 million SNPs and 2.3-3.4 million InDels, mainly located in intergenic regions. Chromosome-level analysis revealed non-uniform distribution patterns, with SNPs predominantly concentrated in central regions, while InDels were primarily enriched in terminal regions across most cultivars. Gene ontology-annotated genes exhibited uneven chromosomal distribution, with SNP-associated genes showing higher density than InDel-associated genes. A total of 28,209 high-confidence homozygous InDels were identified, among which InDels (>= 10 bp)-suitable for molecular marker development-were detected across all cultivars. Based on these findings, nine polymorphic InDel markers were firstly developed for reliable genotyping, facilitating accurate cultivar identification and supporting molecular breeding, seed purity assessment, and germplasm management.

Neuropathological features of Alzheimer's disease include amyloid plaques, neurofibrillary tangles and Lewy bodies, with the former preceding the latter two. However, it is not fully understood how these compound proteinopathies are interconnected. Here, we show that transplantation of amyloid-β oligomer-activated microglia into the striatum of naïve mice was sufficient to generate all the features of Alzheimer's disease, including widespread tauopathy and synucleinopathy, gliosis, neuroinflammation, synapse loss, neuronal death, and cognitive and motor deficits. These pathological features were eliminated by microglia depletion and anti-inflammatory drug administration. Our results suggest the crucial roles of microglia-driven inflammation in development of mixed pathology. This study provides not only mechanistic insights into amyloid-β oligomer-triggered proteinopathies but also a novel animal model recapitulating the salient features of Alzheimer's disease.

Background: This study was conducted to determine color parameters, and identify pharmaceutical constituents and phytochemical characteristics of Korean cultivars (Hongdan, Dasan, and Kosan) of Salvia miltiorrhiza root (Danshen) by crop years compared with those of the Chinese cultivar ["Zhongdanyaozhi No. 1 (ZD1)"].BRMethods and Results: Redness (a*), yellowness (b*), extract yield, salvianolic acid B (Sal B), and tanshinone ⅡA (TanⅡA) were generally higer in Korean cultivars than in ZD1, implying effective quality control with Korean cultivars in Danshen. Sal B and TanⅡA content were found to be the highest in Korean cultivar 'Hongdan' (3-fold higher than 'ZD1') in the 2020 crop year. Sal B was chosen as a major markers to assess Korean Danshen quality. However, Sal B detection was apparently incomplete and insufficient for quality control, because Sal B degradation was crop years dependent, Sal B was degraded to some small molecular phenolic acids, such as caffeic acid, protocatechuic aldehyde, lithospermic acid, and danshensu, which were elucidated by liquid chromatography. Analysis of Pearson's correlation heatmap revealed negative correlation between Sal B and small phenolic acids. The Sal B content of Danshen was correlated to the redness of color parameter, the total terpenoid content, TanⅡA content, suggesting that it would be reasonable to simultaneously detect these characteristics for Danshen quality control.BRConclusions: This study provides constructive and meaningful references for the qualitative and quantitative analyses of S. miltiorrhiza root, which can help establish better quality standards.

Thyroid hormone (TH) imbalance is linked to the pathophysiology of reversible dementia and Alzheimer’s disease (AD). It is unclear whether tissue hypothyroidism occurs in the AD brain and how it affects on AD pathology. We find that decreased iodothyronine deiodinase 2 is correlated with hippocampal hypothyroidism in early AD model mice before TH alterations in the blood. TH deficiency leads to spontaneous activation of microglia in wild-type mice under nonstimulated conditions, resulting in lowered innate immune responses of microglia in response to inflammatory stimuli or amyloid-β. In AD model mice, TH deficiency aggravates AD pathology by reducing the disease-associated microglia population and microglial phagocytosis. We find that TH deficiency reduces microglial ecto-5′-nucleotidase (CD73) and inhibition of CD73 leads to impaired innate immune responses in microglia. Our findings reveal that TH shapes microglial responses to inflammatory stimuli including amyloid-β, and brain hypothyroidism in early AD model mice aggravates AD pathology by microglial dysfunction.

BACKGROUND:In Korea, only Polygala tenuifolia is registered as Polygalae Radix in the pharmacopoeia, while in China, both P. tenuifolia and P. sibirica are used equally. Accurate identification of herbal medicines is crucial for their safety and efficacy, but commercial products are typically sold in dried form, making morphological distinction difficult. Therefore, a quick and accurate method to distinguish P. tenuifolia is necessary for proper utilization of medicinal herb. OBJECTIVE:We aimed to identify specific molecular markers for P. tenuifolia to avoid confusion regarding its pharmacological efficacy and to evaluate the classification of Polygala using plastid phylogenetic data. METHODS:We analyzed the sequences of three species distributed in Korea, P. tenuifolia, P. japonica, and P. sibirica, and assembled their chloroplast genome sequences. Comparative analysis revealed regions of local divergence, and six molecular markers were developed from these hotspots. Additionally, a phylogenetic tree was constructed to determine the phylogenetic positions of the three Polygala species. RESULTS:The marker successfully identified the three Polygala species, and all commercial products and breeding lines tested were confirmed to be P. tenuifolia and recognized as authentic. Phylogenetic analysis revealed that P. tenuifolia forms a distinct cluster from P. sibirica and P. japonica. CONCLUSIONS:We determined the chloroplast genomes of the three Polygala species and performed phylogenetic tree analysis and marker development. Indel markers were developed to identify the critical herbal species, P. tenuifolia. This comprehensive study of the Polygala chloroplast genome provides useful information for P. tenuifolia identification.

Alzheimer's disease (AD) is marked by the presence of intraneuronal neurofibrillary tangles (NFTs), which are primarily composed of hyperphosphorylated tau protein. The locus coeruleus (LC), the brain's main source of norepinephrine (NE), is one of the earliest regions to develop NFTs and experience neurodegeneration in AD. While LC-derived NE plays beneficial roles in cognition, emotion, locomotion, and the sleep-wake cycle, its impact on tau pathology is unclear. To explore this relationship, we administered intraperitoneal injections of either N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), a selective neurotoxin for noradrenergic neurons, or reboxetine (RBX), a norepinephrine reuptake inhibitor, to decrease or increase NE levels, respectively, in early tau transgenic mice expressing mutant human P301L tau (ADLPTau) for two months. Only the RBX-treated mice exhibited cognitive deficits, as evidenced by their performance in the Y-maze, novel object recognition, and contextual fear conditioning tests. Immunohistochemical analysis revealed increased hyperphosphorylated tau aggregates in the LC and hippocampus of the RBX-treated mice. Furthermore, neuronal apoptosis was observed in the hippocampal CA1 region of these mice. Western blotting showed that RBX injections led to the overactivation of tau kinases PKA and GSK3β, resulting in hyperphosphorylated tau, neuronal loss, and cognitive impairments. Consistent with these findings, human brain organoids exposed to higher NE concentrations also displayed elevated hyperphosphorylated tau and increased activity of the same tau kinases. These findings suggest that excessive NE exposure accelerates tau pathology by overactivating the tau kinases. Thus, modulating NE levels in the brain via the LC-NE system could be a potential therapeutic strategy for tau-related AD.

The ability to generate visceral sensory neurons (VSN) from induced pluripotent stem (iPS) cells may help to gain insights into how the gut-nerve-brain axis is involved in neurological disorders. We established a protocol to differentiate human iPS-cell-derived visceral sensory ganglion organoids (VSGOs). VSGOs exhibit canonical VSN markers, and single-cell RNA sequencing revealed heterogenous molecular signatures and developmental trajectories of VSGOs aligned with native VSN. We integrated VSGOs with human colon organoids on a microfluidic device and applied this axis-on-a-chip model to Alzheimer's disease. Our results suggest that VSN could be a potential mediator for propagating gut-derived amyloid and tau to the brain in an APOE4- and LRP1-dependent manner. Furthermore, our approach was extended to include patient-derived iPS cells, which demonstrated a strong correlation with clinical data. A protocol for differentiating visceral sensory ganglion organoids from induced pluripotent stem cells allows the establishment of an in vitro model for the gut-visceral nerve-brain axis and study of the propagation of pathogenic proteins involved in Alzheimer's disease along the vagus nerve.

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta-amyloid (Aβ) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aβ) plaques remains unknown. Here, using advanced 2D/3D/4D co-culture systems with loss-of-function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aβ via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aβ plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR-Cas9-based APOE4 lines) and familial (APPNL-G-F/MAPT double knock-in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer-positive Aβ plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aβ plaques in the context of the presence of ePtdSer during AD progression.

Abnormal glial activation promotes neurodegeneration in Alzheimer's disease (AD), the most common cause of dementia. Stimulation of the cGAS-STING pathway induces microglial dysfunction and sterile inflammation, which exacerbates AD. We showed that inhibiting STING activation can control microglia and ameliorate a wide spectrum of AD symptoms. The cGAS-STING pathway is required for the detection of ectopic DNA and the subsequent immune response. Amyloid-β (Aβ) and tau induce mitochondrial stress, which causes DNA to be released into the cytoplasm of microglia. cGAS and STING are highly expressed in Aβ plaque-associated microglia, and neuronal STING is upregulated in the brains of AD model animals. The presence of the APOE ε4 allele, an AD risk factor, also upregulated both proteins. STING activation was necessary for microglial NLRP3 activation, proinflammatory responses, and type-I-interferon responses. Pharmacological STING inhibition reduced a wide range of AD pathogenic features in AppNL-G-F/hTau double-knock-in mice. An unanticipated transcriptome shift in microglia reduced gliosis and cerebral inflammation. Significant reductions in the Aβ load, tau phosphorylation, and microglial synapse engulfment prevented memory loss. To summarize, our study describes the pathogenic mechanism of STING activation as well as its potential as a therapeutic target in AD.

Agastache is a genus of perennial herbaceous plants belonging to the mint family, Lamiaceae. Several Agastache species are commercially cultivated and used as medicinal, culinary, and ornamental plants. However, information on the genetic diversity and population structure of the species remains unclear. In the present study, genetic diversity within Agastache species was analyzed using simple sequence repeat (SSR) markers. In this study, 249,746 SSRs were identified in the A. rugosa genome and primer pairs were designed for 56,675 SSRs. The majority of SSR repeat types were dinucleotides (60.65%), followed by trinucleotides (12.38%), and pentanucleotides (12.10%). PCR conditions were established for 250 primer pairs, 111 of which were found to be polymorphic in A. rugosa germplasm. The number of alleles (NA) ranged from 2 to 19, major allele frequency (MAF) ranged from 0.11 to 0.95, observed heterozygosity (HO) ranged from 0 to 0.89, and polymorphic information content (PIC) ranged from 0.09 to 0.92. Cross-species amplification of SSRs markers in other Agastache species showed amplification rates of 82.6% for A. foeniculum and 78.1% in A. urticifolia, with an average of 80.37%. Cluster analysis of the 19 A. rugosa accessions using SSRs markers revealed four major clusters, and population STRUCTURE analysis using 79 SSRs markers revealed three groups and three subgroups among the A. rugosa populations. The SSRs markers developed can contribute to applications such as varietal identification, genetic diversity analysis, and population structure analysis of A. rugosa germplasm.