TL;DR
Seipin is identified as a novel regulator of ferroptosis in the pathogenesis of AD and the potential of the BSCL2-glycine-ferroptosis axis as a therapeutic target is underscored.
Alzheimer’s disease (AD) is marked by progressive neuronal deterioration resulting from the convergence of mitochondrial dysfunction, disrupted iron homeostasis, elevated oxidative stress, and compromised cellular quality-control systems. In addition to the well-established roles of amyloid-a accumulation and tau pathology, mounting evidence implicates ferroptosis- an iron-dependent, lipid peroxidation-driven mode of regulated cell death-together with defects in autophagy and mitophagy, as tightly interconnected contributors to neuronal degeneration. Despite increasing recognition of this pathological interplay, therapeutic approaches capable of concurrently targeting these mechanisms remain scarce. Berberine, a naturally occurring isoquinoline alkaloid, has attracted interest as a pleiotropic compound with reported antioxidant, mitochondria-stabilizing, and autophagy-modulatory activities. In the present study, a computational systems biology approach was employed to investigate the interplay between ferroptosis, autophagy, and mitophagy in Alzheimer’s disease. Differentially expressed genes were integrated with curated pathway-specific gene sets to identify key overlapping regulators within the FMA axis. Functional enrichment and network-level analyses revealed that these genes are involved in pathways associated with oxidative stress, mitochondrial quality control, and impaired proteostasis. Furthermore, molecular docking analysis suggested that berberine exhibits favourable binding interactions with selected hub targets, supporting its potential role in modulating interconnected cell death and survival pathways. Collectively, these findings highlight the coordinated dysregulation of the FMA axis in AD and provide a computational basis for exploring multi-target therapeutic strategies.
Dysregulation of iron homeostasis and ferroptosis is increasingly implicated in Alzheimer's disease (AD) pathology. Lactotransferrin (LTF) and hepcidin (HAMP) are key regulators of neuronal iron metabolism, but their role in AD-related ferroptosis remains unclear. Bioinformatics analysis of hippocampal RNA-sequencing data from AD patients and healthy controls identified differentially expressed genes (DEGs) associated with iron metabolism. SH-SY5Y cells were treated with Aβ oligomers to establish AD cell models and further subjected to siRNA-mediated knockdown of LTF or HAMP. Ferroptosis was evaluated using Fe²⁺ accumulation, lipid reactive oxygen species (ROS), mitochondrial morphology, MDA/GSH levels, and the expression of core ferroptosis regulators (GPX4, SLC7A11, ACSL4). Cell viability, LDH release, and apoptosis were also assessed. Bioinformatics analysis revealed LTF and HAMP as key DEGs related to iron homeostasis, potentially linked to ferroptosis in AD. In vitro, Aβ treatment decreased LTF and HAMP expression, induced Fe²⁺ accumulation, oxidative stress, mitochondrial damage, and ferroptotic cell death. Knockdown of LTF or HAMP further exacerbated these effects, while treatment with the ferroptosis inhibitor Fer-1 partially restored cellular homeostasis and viability. The data suggest a regulatory role of LTF and HAMP in neuronal ferroptosis. Notably, hyper-expression of LTF and HAMP observed in post-mortem AD hippocampal samples likely reflects compensatory negative feedback mechanisms in late-stage disease. LTF and HAMP act as protective modulators against neuronal ferroptosis in AD. Their early downregulation promotes iron overload and oxidative stress, whereas compensatory upregulation in vivo delays ferroptosis. Targeting LTF and HAMP-mediated pathways may provide novel therapeutic strategies for mitigating AD progression.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Increasing evidence suggests that impaired glucose utilization is a major contributor to AD pathogenesis. Neurons preferentially use glucose through the pentose phosphate pathway (PPP). In AD, the flux through the PPP is significantly reduced; however, the underlying mechanism is still elusive. This study was aimed to elucidate how PPP was affected in AD and its contribution to the AD pathogenesis. Proteomic analyses of temporal cortex synaptosomes from AD patients and controls were conducted to identify dysregulated pathways and significantly affected proteins. Functional analysis was performed by knockdown or restoration of protein expression in primary cultured neurons, as well as in wild-type and 5 × FAD mice. Pseudotargeted metabolomics and biochemical, molecular, electrophysiological and behavioral assessments were performed to evaluate metabolic characteristics, redox status, mitochondrial function, synaptic plasticity and cognition. Proteomic analysis of synaptic compartments identified glucose metabolism as the most significantly dysregulated functional network in AD. Further, transaldolase 1 (TALDO1), a rate-limiting enzyme in the PPP, was identified as a key enzyme affected in AD. TALDO1 was markedly downregulated at the early stage of AD. Downregulation of TALDO1 reduced glucose metabolism by inhibiting the PPP, TCA cycle and oxidative phosphorylation, causing broad metabolic collapse. Further, downregulation of TALDO1 depleted the nicotinamide adenine dinucleotide phosphate and glutathione pools, weakening antioxidant defense, thus resulting in mitochondria impairment and reduced energy supply. These collectively drive synaptic dysfunction and cognitive decline. Conversely, restoring TALDO1 expression in 5 × FAD mice improved glucose uptake, mitigated oxidative stress, restored metabolic homeostasis, and rescued neuronal and cognitive functions. These findings identify TALDO1 as a key regulator of the impaired PPP in AD and may represent a promising therapeutic target for restoring neuronal metabolic homeostasis and function.
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation, oxidative stress, and excitotoxicity. Ferroptosis and N-methyl-D-aspartate (NMDA) receptor activity,may be interconnected in the pathogenesis of Aβ accumulation and associated neurodegeneration in AD. However, the interplay between these pathways remains poorly understood and underexplored for therapeutic intervention against the AD. The review aims to explore the shared molecular triggers of ferroptosis and NMDA receptor overactivation, including the roles of iron, glutamate overload, calcium dysregulation, and reactive oxygen species (ROS) accumulation. We further highlighted the convergent consequences of these processes on mitochondrial dysfunction, lipid peroxidation, and their impact on Aβ pathology. Particular attention is given to P-glycoprotein (P-gp), an efflux transporter involved in the Aβ clearance at the blood-brain barrier, whose expression and function may be modulated by oxidative stress, iron homeostasis, and NMDA receptor signaling. Emerging evidence indicated that ferroptosis and NMDA receptor activity may disrupt P-gp function, thereby impairing Aβ clearance and promoting its accumulation in the AD. Overall, the review elucidates the molecular mechanisms linking ferroptosis and NMDA receptor overactivation and their impact on P-gp-mediated Aβ transport in the AD, providing integrated mechanisms and harnessing their potential for AD therapeutics.
Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.
Summary Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with limited therapeutic options. Here, we report that tuberostemonine (Tub), an alkaloid from Stemona tuberosa, exerts neuroprotective effects in AD models. In Aβ1-42-treated PC12 cells, Tub reduced cytotoxicity, apoptosis, and oxidative stress while restoring mitochondrial function. In APP/PS1 transgenic mice, Tub administration improved cognitive performance, reduced amyloid-β plaque deposition, attenuated microglial activation, and attenuated neuronal loss, with efficacy superior to donepezil. Mechanistically, Tub selectively inhibited p38 MAPK phosphorylation without affecting ERK or JNK pathways, as confirmed by pharmacological inhibition and activation experiments. These findings identify Tub as a promising multi-target natural compound for AD intervention through p38 MAPK pathway modulation.
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