The review organizes Alzheimer’s pathology into seven interconnected pillars: the amyloid-beta cascade, tau abnormalities, neuroinflammation, regulated cell death, synaptic plasticity impairment, gut microbiota-brain axis imbalance, and oxidative stress. Each pillar alone has been the target of major drug programs, and each alone has largely disappointed. The amyloid hypothesis, which dominated the field for decades, produced antibodies that clear plaques but deliver only modest clinical benefit, fueling debate about whether attacking one node of a network can ever halt a systems-level disease. The authors argue that this is precisely where TCM’s multi-component, multi-target character becomes an advantage rather than a liability, because a single herbal formula can modulate dozens of molecular nodes at once.

At the top of the review’s mechanistic hierarchy sit two molecular hubs: glycogen synthase kinase 3 beta, known as GSK-3β, and nuclear factor kappa-B, or NF-κB. GSK-3β is the principal kinase that tags tau proteins with phosphate groups, driving them to detach from microtubules and clump into the neurofibrillary tangles that correlate so tightly with cognitive decline. NF-κB, meanwhile, is the master switch of inflammation, sitting at the intersection of amyloid signaling and the activation of microglia, the brain’s immune cells. Because these two hubs link the protein-aggregation side of Alzheimer’s to its inflammatory side, the review positions them as the most strategically valuable targets in the entire network, and notes that many TCM compounds converge on them.

The evidence for this convergence is drawn from a striking range of plant-derived molecules. Tanshinone IIA, a diterpenoid from the root of Salvia miltiorrhiza, has been shown in APP/PS1 transgenic mice to regulate GSK-3β-related signaling and ameliorate memory impairment, while independently suppressing the RAGE/NF-κB inflammatory pathway in cell and animal models. Curcumin, the golden pigment of turmeric, inhibits the HMGB1-RAGE/TLR4-NF-κB cascade in the hippocampus of Alzheimer’s model mice and also activates AMPK, an energy-sensing kinase that guards metabolic and mitochondrial homeostasis. Hesperidin and its aglycone hesperetin, flavonoids from citrus peel, activate Akt/Nrf2 antioxidant signaling while dampening RAGE/NF-κB, effectively pushing the same network in two protective directions at once.

Inflammation receives particularly detailed treatment in the review. Microglial activation and the NLRP3 inflammasome, a molecular machine that triggers the inflammatory form of cell death called pyroptosis, have emerged as central amplifiers of neurodegeneration. Baicalin, a flavone from Scutellaria baicalensis, protects neurons by suppressing both NLRP3 inflammasomes and TLR4/NF-κB signaling, while resveratrol blocks Aβ-induced microglial activation through the TXNIP/TRX/NLRP3 pathway. Forsythoside B attenuates memory impairment by inhibiting NF-κB signaling, and the multi-herb formula Kai-Xin-San ameliorates Alzheimer’s-related neuropathology in APP/PS1 mice via the mitochondrial autophagy-NLRP3 inflammasome axis, with a related study implicating the SIRT3/NLRP3 pathway in its protection of mitochondrial function. The pattern is consistent: rather than blocking one cytokine, these compounds throttle the upstream switches that produce interleukin-6, interleukin-1 beta, and tumor necrosis factor alpha together.

Cell death itself is another domain where the review finds TCM acting across multiple modalities. Beyond apoptosis, Alzheimer’s brains show ferroptosis, an iron-dependent death driven by lipid peroxidation and loss of the antioxidant enzyme GPX4, as well as pyroptosis mediated by caspase-1 cleavage of gasdermin D, and necroptosis regulated by RIPK1 complexes. The PINK1/Parkin pathway, which tags damaged mitochondria for removal by mitophagy, is frequently defective in the disease, allowing dysfunctional mitochondria to accumulate and spew reactive oxygen species. Compounds such as the combination of beta-asarone and icariin have been reported to reverse cognitive deficits by promoting mitophagy, while galangin rescues amyloid-beta-induced mitophagy impairment in brain organoid models. By restoring cellular quality control rather than merely blocking death executioners, these interventions address death pathways upstream of the point of no return.

Synaptic failure, arguably the strongest correlate of cognitive decline, is governed by molecules such as brain-derived neurotrophic factor, or BDNF, and the postsynaptic scaffold protein PSD-95. Recent work shows that PSD-95 can physically protect synapses from beta-amyloid toxicity, and that multivalent tau/PSD-95 interactions can disrupt the postsynaptic density. On the TCM side, Suan-Zao-Ren Decoction ameliorates synaptic plasticity in APP/PS1 mice by inhibiting amyloid deposition and JAK2/STAT3 signaling, while the Chinese herbal compound Jinsiwei improves synaptic plasticity in a sporadic Alzheimer’s model induced by streptozotocin. Hesperidin has been shown to improve memory by enhancing neurogenesis, and sesame lignans elevate BDNF expression alongside anti-cholinesterase activity, suggesting that herbal compounds can rebuild synaptic architecture rather than simply slow its erosion.

Perhaps the most contemporary section of the review concerns the gut microbiota-brain axis. Germ-free studies have shown that amyloid pathology can be reduced in the absence of gut microbes, and that transferring a healthy microbiota into Alzheimer’s model animals reduces both amyloid and tau pathology. Gut-derived beta-amyloid itself has been proposed as a centerpiece of gut-brain communication in the disease, and gut microbiota have been shown to regulate Alzheimer’s pathologies through polyunsaturated fatty acid-associated neuroinflammation. TCM formulas appear well suited to this axis: Qifu Yin regulates intestinal microbiota in mice with memory impairment, and the classical formula Huang-Lian-Jie-Du Decoction acts on oxidative stress and the AMPK-SIRT1 pathway in Alzheimer’s rats, linking metabolic, redox, and microbial regulation in a single intervention.

The redox thread ties the whole network together. Oxidative stress has been proposed to occur prior to amyloid plaque formation and tau phosphorylation, with glutathione depletion and metal ion dysregulation as early events. The Nrf2/HO-1 pathway is the cell’s primary antioxidant defense, and multiple TCM molecules converge on it: rhynchophylline from the cat’s claw vine activates Nrf2-ARE signaling against amyloid-induced oxidative damage, platycodin D simultaneously suppresses TLR4/NF-κB and activates Nrf2/HO-1 in microglial cells, and Qifu-yin activates the Keap1/Nrf2/ARE axis to ameliorate synaptic injury in APP/PS1 mice. Meanwhile SIRT1, activated by resveratrol and targeted by tanshinone IIA in the context of endoplasmic reticulum stress, regulates both inflammation and mitochondrial biogenesis, positioning the AMPK-SIRT1-Nrf2 module as the metabolic and redox control center that TCM compounds repeatedly engage.

The review’s authors are careful to frame their synthesis as a direction rather than a verdict. Human clinical evidence remains thinner than the preclinical literature, although randomized controlled trials such as one testing the Huannao Yicong Formula against donepezil in mild-to-moderate Alzheimer’s patients and a pilot trial of Kami-guibi-tang for mild cognitive impairment point toward translational potential. Standardization of herbal preparations, identification of active constituents, and rigorous multi-center trials remain essential hurdles. Yet the conceptual contribution is clear and, to many researchers, compelling: by concurrently modulating GSK-3β and NF-κB hubs, the AMPK-SIRT1-Nrf2 metabolic core, PINK1/Parkin mitophagy, and the BDNF/PSD-95 synaptic machinery, traditional Chinese medicine establishes a synergistic therapeutic network that reduces amyloid deposition, attenuates tau hyperphosphorylation, and mitigates neuronal damage in ways that single-target drugs cannot replicate. As the search for effective Alzheimer’s therapies continues, the ancient pharmacopeia may prove to hold not a miracle cure, but a blueprint for treating a network disease as a network.

Subject of Research: Multi-target mechanisms of traditional Chinese medicine in Alzheimer's disease therapy

Article Title: Traditional Chinese medicine for Alzheimer’s disease: pathological mechanisms and multi-target interventions

Article References: Zhang, Y., Song, R., Wang, J., Chen, B., Sun, H., Ren, X., Ju, L., Feng, X., Wang, X., & Qin, G. (2026). Traditional Chinese medicine for Alzheimer’s disease: pathological mechanisms and multi-target interventions. 3 Biotech, 16(10), Article 449. https://doi.org/10.1007/s13205-026-05078-2

Image Credits: AI Generated

DOI: 10.1007/s13205-026-05078-2

Keywords: Alzheimer's disease, traditional Chinese medicine, amyloid-beta, tau hyperphosphorylation, neuroinflammation, GSK-3β, NF-κB, NLRP3 inflammasome, mitophagy, gut microbiota-brain axis, oxidative stress, synaptic plasticity

The logic of the target is compelling. GSK-3β is a constitutively active serine/threonine kinase that phosphorylates more than 100 substrates, governing glucose disposal, lipid metabolism, inflammation and fibrogenesis. Under normal conditions, insulin signalling activates the PI3K/Akt cascade, which phosphorylates GSK-3β at Ser9 and switches it off, freeing glycogen synthase to build glycogen stores in liver and muscle. In insulin resistance—the shared root of both type 2 diabetes and MASH—that brake fails. Hyperactive GSK-3β keeps glycogen synthase locked in its inactive, phosphorylated state, degrades insulin receptor substrate-1 through inhibitory serine phosphorylation, stabilizes the gluconeogenic factors PGC-1α and FOXO1, and drives hepatic glucose output. In the liver, it fuels SREBP-1c-mediated lipogenesis, undermines AMPK-driven fatty acid oxidation, sustains NF-κB inflammatory signalling and promotes TGF-β/Smad-driven collagen deposition in hepatic stellate cells. Preclinical rodent studies have repeatedly shown that inhibiting or deleting GSK-3β improves insulin sensitivity and blunts steatosis, inflammation and fibrosis.

Existing GSK-3 inhibitors have not translated into metabolic medicine. Lithium is non-selective with a narrow therapeutic window; AR-A014418 remains a biochemical tool compound; tideglusib, a clinical candidate for neurodegenerative disease, crosses the blood–brain barrier—an undesirable trait for chronic peripheral therapy—and LY2090314 and elraglusib have been pursued in oncology. Shared obstacles include poor selectivity between the GSK-3α and GSK-3β isoforms, whose ATP sites are nearly identical, and the theoretical oncogenic risk of sustained β-catenin stabilization. These gaps motivated the research team, led by Lateef Bello and colleagues at Adekunle Ajasin University in Nigeria, to search for peripherally restricted, structurally novel scaffolds in microbial chemistry.

The screening cascade began with 36,545 microbial natural products from the Natural Products Atlas. Applying Lipinski’s Rule of Five in DataWarrior retained 21,390 drug-like compounds—58.5 percent of the library—suggesting that microbial metabolites occupy an unusually favourable region of chemical space. A four-feature energy-optimized pharmacophore, derived from the crystal structure of human GSK-3β bound to the ATP-competitive inhibitor 7YG (PDB ID 4ACC), then filtered the library down to just 218 compounds matching three aromatic ring features and one hydrogen-bond donor. This ligand-based step eliminated 99 percent of candidates before any computationally expensive docking was attempted.

Critical to the study’s credibility was rigorous protocol validation. Re-docking the co-crystallized ligand reproduced the crystallographic pose with a root mean square deviation of 0.8357 angstroms, well within the conventional 2.0 angstrom cutoff. Enrichment analysis using 25 known GSK-3β inhibitors from ChEMBL and 1,255 generated decoys demonstrated exceptional discriminatory power: a ROC value of 0.98, an area under the curve of 0.97, and full recovery of all active compounds within the top 5 percent of the ranked list—a twenty-fold enrichment over random selection.

Structure-based docking then proceeded through three escalating precision tiers. High-throughput virtual screening cut the 218 pharmacophore hits to 178; standard precision docking at a −6.0 kcal/mol threshold retained 88 compounds, and a −6.5 kcal/mol cut kept 69. Extra-precision (XP) docking of the 50 best-ranked compounds ultimately yielded six hits—NPA011425, NPA014875, NPA020257, NPA004276, NPA034843 and NPA036064—with XP scores ranging from −6.858 to −11.059 kcal/mol. Every one of them outperformed the co-crystallized reference ligand (−6.455 kcal/mol), AR-A014418 (−5.929 kcal/mol) and tideglusib (−5.895 kcal/mol). All six formed hydrogen bonds with the conserved hinge-region residues Asp133, Val135 and Pro136 while packing against the hydrophobic ATP-binding pocket lined by Ile62, Val70, Ala83, Leu132 and Leu188, a signature consistent with ATP-competitive inhibition.

Independent scoring methods corroborated the docking results. Molecular Mechanics Generalized Born Surface Area (MMGBSA) calculations gave NPA014875 a binding free energy of −62.67 kcal/mol, essentially matching the native ligand’s −63.15 kcal/mol and far exceeding the reference inhibitors. Induced Fit Docking, which permits the binding site to relax around each ligand, confirmed receptor-adaptive binding: NPA014875 scored −730.74 kcal/mol, comparable to AR-A014418 and superior to both the reference ligand and tideglusib, while several compounds gained new interactions—such as π–π stacking with Phe67 or cationic contacts with Arg141—once side-chain flexibility was introduced. A machine-learning AutoQSAR model, trained on 1,500 curated ChEMBL inhibitors with an R-squared of 0.7123, predicted the highest potency for NPA020257, with a pIC50 of 6.82.

The pharmacokinetic and safety picture was equally encouraging. All six hits showed zero Lipinski violations, molecular weights between 308 and 430 g/mol, and favourable oral bioavailability scores. Crucially, none was predicted to cross the blood–brain barrier, whereas tideglusib was—a property the authors highlight as a therapeutic advantage, since central GSK-3β inhibition has been linked to neuropsychiatric effects and circadian disruption. Four of the six compounds showed no predicted inhibition across the five major cytochrome P450 isoforms, an important consideration for diabetic patients on polypharmacy. Toxicity predictions with ProTox-3.0 assigned all hits to class IV, with none predicted cytotoxic or cardiotoxic. The only flags were specific: NPA011425 alone was predicted hepatotoxic, NPA004276 showed oestrogen-receptor activity, and NPA014875 and NPA004276 were predicted active in mitochondrial membrane potential assays—a liability that matters in MASH, where hepatocyte mitochondrial reserve is already compromised.

Reading all five evaluation axes together—docking score, binding free energy, induced-fit performance, predicted potency and toxicity liabilities—the study names NPA020257 and NPA034843 as the most balanced candidates, both carrying zero major predicted liabilities. NPA014875 stands out as the strongest calculated binder but requires lead optimization against its mitochondrial flag; NPA011425 and NPA004276 remain affinity-rich chemotypes with clearly defined medicinal-chemistry objectives; and NPA036064 offers the cleanest safety profile as a backup scaffold. The authors are careful to frame the composite ranking as a triage map rather than a verdict, keeping all six compounds in play.

The limitations are candidly acknowledged. Every finding is computational and awaits experimental confirmation: enzymatic GSK-3β assays, kinase selectivity profiling against GSK-3α and broader panels, molecular dynamics simulations of complex stability, and validation of the predicted ADMET profiles in cellular and animal models of diabetes and MASH. The AutoQSAR model was trained largely on synthetic inhibitors, and no formal applicability-domain check was performed for the natural product hits. Still, the work demonstrates the power of a disciplined virtual screening cascade to convert a massive natural product database into a short, chemically diverse list of prioritized hits—hits that, if validated, could one day deliver what current medicine cannot: a single molecule that simultaneously restores insulin sensitivity and halts the inflammatory, fibrotic progression of fatty liver disease.

Subject of Research: Computational identification of microbial natural product inhibitors of glycogen synthase kinase 3 beta as candidate dual therapeutics for type 2 diabetes mellitus and MASH.

Article Title: Computational screening of the natural products atlas identifies potential glycogen synthase kinase 3 beta inhibitors as candidate therapeutics for type 2 diabetes mellitus and MASH

Article References: Bello, L., Nwankwo, D. O., Shodehinde, S. A., Akerele, G. P., Okuntimehin, B., Ogunjobi, E. G., Awelewa, O. V., Abass, O. A., Oginni, S. A., & Olubode, S. O. (2026). Computational screening of the natural products atlas identifies potential glycogen synthase kinase 3 beta inhibitors as candidate therapeutics for type 2 diabetes mellitus and MASH. Discover Chemistry, 3(1), Article 536. https://doi.org/10.1007/s44371-026-00989-8

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00989-8

Keywords: GSK-3β, type 2 diabetes, MASH, Natural Products Atlas, virtual screening, molecular docking, MMGBSA, induced fit docking, AutoQSAR, ADMET, drug discovery, microbial natural products

GSK-3β has occupied a central place in Alzheimer’s research for decades. The enzyme is a serine/threonine kinase that phosphorylates a wide array of substrates, including the tau protein whose hyperphosphorylated tangles are a hallmark of the disease. In a mouse model engineered to overexpress GSK-3β, previous work had already documented a decrease in dendritic spine density in the dentate gyrus, the gateway through which cortical information enters the hippocampus. What remained unknown was how the rest of the trisynaptic circuit—the entorhinal cortex, CA3, and CA1—responds to elevated levels of this kinase. The new study, led by María Llorens-Martín and colleagues at the Centro de Biología Molecular Severo Ochoa in Madrid, set out to fill that gap.

To capture the fine structure of neurons, the researchers turned to a classical but technically demanding technique: intracellular injection of Lucifer Yellow, a fluorescent dye that fills individual neurons in fixed tissue and reveals their dendritic trees and spines in exquisite detail. Using this method, the team analyzed dendritic spine morphology and density on both apical and basal dendrites of pyramidal neurons in the entorhinal cortex, CA3, and CA1, comparing wild-type mice with mice overexpressing GSK-3β. Spines—the tiny protrusions studding dendrites where most excitatory synapses reside—come in distinct morphological classes, including mushroom, thin, and stubby forms, each thought to reflect different stages of synaptic maturity and stability. The head diameter and length of each spine type were quantified, alongside the overall density of spines.

The first striking result came from the wild-type animals themselves. Even in healthy brains, the study found intrinsic differences in spine density and in the distribution of spine types between apical and basal dendrites across the different regions of the trisynaptic circuit. This baseline regional heterogeneity matters, because it establishes that apical and basal dendrites— which receive different complements of afferent inputs—are not interchangeable substrates. Any pathological process acting on the circuit will therefore be superimposed on a landscape already patterned by region- and compartment-specific wiring.

When the researchers compared the GSK-3β-overexpressing mice to their wild-type littermates, a clear hierarchy of vulnerability emerged. The entorhinal cortex, despite being the region typically hit earliest by Alzheimer’s pathology in humans, showed only subtle morphological changes in this model, a finding the authors interpret as a form of partial structural resilience. The CA3 region, likewise, presented minimal alterations overall—although here the basal dendrites were more affected than their apical counterparts, a pattern the authors attribute to the differential inputs these two dendritic compartments receive. In sharp contrast, CA1 stood out as the most affected region of the entire circuit, a result consistent with the well-documented vulnerability of CA1 to Alzheimer’s disease pathology in both human patients and animal models.

Beyond spine shape, the study probed the functional architecture of the circuit by examining excitatory innervation. The researchers stained for vesicular glutamate transporter 1, or VGlut1, a marker of excitatory presynaptic boutons, and measured the percentage of area occupied by VGlut1-positive terminals around the dendritic compartments. In both CA1 and the basal dendrites of CA3, the GSK-3β-overexpressing mice showed a reduced percentage of area occupied by VGlut1-positive boutons, indicating a loss of excitatory innervation. Because excitatory drive is the currency of synaptic plasticity—the cellular substrate of learning and memory—this loss suggests that GSK-3β overexpression does not merely remodel the shape of spines but actively disrupts the connectivity needed for plasticity to occur.

The regional selectivity of these alterations carries significant implications for how scientists think about the progression of Alzheimer’s disease. Rather than a diffuse, homogeneous degeneration of the hippocampal formation, the data support a model in which specific subregions and even specific dendritic compartments are differentially susceptible to a single molecular insult. The vulnerability of CA1 is particularly noteworthy: this region serves as the major output hub of the hippocampus, relaying processed information back to the cortex. Structural compromise at this node, combined with lost excitatory innervation, could plausibly undermine the coherence of the entire memory circuit even while upstream regions such as the entorhinal cortex and CA3 appear comparatively preserved.

The study also underscores the value of apical–basal comparisons. In CA3, basal dendrites were more affected than apical dendrites, likely reflecting the different sources of input they receive—apical dendrites in CA3 are heavily targeted by perforant path fibers from the entorhinal cortex and associational inputs, whereas basal dendrites sample a different mix of local and long-range afferents. That GSK-3β overexpression left a compartment-specific fingerprint on the circuit suggests that the enzyme’s effects are mediated not only by intrinsic neuronal properties but also by the identity of the inputs each dendrite integrates. This level of resolution would have been impossible with bulk tissue measurements and highlights why single-cell anatomy remains indispensable in neuroscience.

Methodologically, the work relied on carefully characterized mouse cohorts, with the GSK-3β-overexpressing model validated by β-galactosidase and NeuN staining to confirm transgene expression and neuronal counts across the entorhinal cortex, CA3, and CA1. Excitatory and inhibitory balance was further assessed by quantifying GAD65-positive inhibitory boutons alongside VGlut1-positive excitatory terminals, allowing the team to compute ratios that capture the excitatory–inhibitory landscape around each dendritic compartment. Statistical comparisons were performed across regions, genotypes, and dendritic compartments, with sample sizes of four to five animals per group for the various analyses, lending statistical weight to the observed regional differences.

Taken together, the study paints a nuanced picture of GSK-3β as a driver of regionally selective synaptic deterioration within the memory circuit. By demonstrating that the entorhinal cortex retains partial structural resilience, that CA3 is largely spared except for its basal compartment, and that CA1 is the most affected node, the researchers provide a cellular framework for understanding why certain hippocampal areas fail early in Alzheimer’s disease while others endure. The loss of excitatory innervation in CA1 and basal CA3 further implicates disrupted synaptic plasticity as a downstream consequence of kinase overexpression. As the field continues to pursue GSK-3β as a therapeutic target, these findings caution that interventions will need to account for the striking regional and compartmental heterogeneity of the hippocampal circuit—and they offer a detailed anatomical benchmark against which future protective strategies can be measured.

Subject of Research: Regional dendritic spine and innervation changes caused by GSK-3β overexpression in the hippocampal trisynaptic circuit of a mouse model relevant to Alzheimer's disease.

Article Title: Regional differences in dendritic spine morphology and innervation of the trisynaptic circuit of a mouse model of GSK-3β overexpression

Article References: Alonso-Moreno, M. C., Terreros-Roncal, J., Rodríguez-Moreno, C. B., Ávila, J., & Llorens-Martín, M. (2026). Regional differences in dendritic spine morphology and innervation of the trisynaptic circuit of a mouse model of GSK-3β overexpression. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06304-z

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06304-z

Keywords: Alzheimer's disease, GSK-3β, dendritic spines, hippocampus, trisynaptic circuit, entorhinal cortex, CA1, CA3, pyramidal neurons, VGlut1, synaptic plasticity, mouse model