Alzheimer's Disease Therapy Research Articles

Poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate)-based microspheres as a sustained platform for Huperzine A delivery for alzheimer's disease therapy

Huperzine A (HupA) is used in Alzheimer's disease (AD) therapy for its effective inhibition of acetylcholinesterase (AChE) and enhancement of cholinergic neuronal function. However, direct oral administration and injection of HupA cause side effects like nausea, anorexia, and rapid metabolism. Using a tripolymer, poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate (PBVHx), from the polyhydroxyalkanoate (PHA) family synthesized via synthetic biology, we present a novel AD therapy strategy with peritoneally administered PBVHx microspheres loaded with HupA (HupA-PBVHxMs). This approach extends HupA's metabolic duration in the blood and brain, enhancing AChE inhibition efficacy. Uniformly sized HupA-PBVHxMs, created using microfluidics and rotary evaporation, show up to 70.4 % drug encapsulation efficiency, sustained HupA release for 40 days, reduced neurotoxicity from Aβ25–35, and maintained in vivo HupA supply and AChE inhibition for over 20 days. In cognitive tests, HupA-PBVHxMs improved function in AD mice. Thus, PBVHx microspheres with slower HupA release and lower biotoxicity offer a superior platform for sustained AChE inhibitor release, outperforming commercial PLGA microspheres.

Design, synthesis, and pharmacological characterization of sulfonylurea-based NLRP3 inhibitors: Towards an effective therapeutic strategy for Alzheimer's disease

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that severely diminishes the quality of life for millions. The NLRP3 inflammasome, a critical mediator of inflammation, has emerged as a promising therapeutic target for AD. In this study, we report the development and optimization of a novel series of sulfonylurea-based NLRP3 inhibitors, with a focus on compound MC1 for the treatment of AD. Utilizing the co-crystal structure of MCC950 in complex with NLRP3 as a guide, we employed a hybrid approach of computer-aided drug design and traditional medicinal chemistry to perform two iterative optimization cycles. This strategy led to the synthesis and evaluation of 40 sulfonylurea derivatives, culminating in the identification of MC1 as the lead candidate. MC1 exhibited enhanced NLRP3 inhibitory activity and demonstrated high binding affinity to NLRP3, effectively blocking NLRP3 activation induced by diverse stimuli such as ATP and Nigericin, without perturbing upstream processes like reactive oxygen species (ROS) generation. In vivo experiments in AD mouse models revealed that MC1 significantly ameliorated cognitive deficits, surpassing the performance of MCC950. Importantly, MC1 showed no signs of hepatotoxicity or adverse effects on the central nervous system. These findings suggest that MC1 holds strong potential as a lead compound for further development in AD therapy, providing a new scaffold for NLRP3 inhibition with improved safety and efficacy profiles.

In silico, In vitro, and In vivo Evaluation of the Anti-alzheimer’s Activity of Berberine

Background: Alzheimer’s disease (AD), a progressive neurodegenerative disease for which there is no effective cure is among the leading causes of death worldwide. Objectives: To investigate the potential anti-AD activity of berberine (BBR). Methods: In silico assessment included molecular docking and ADMET prediction. BBR’s in vitro inhibitory activity of the target selected from docking results was assessed via colorimetric inhibitor screening assay. BBR’s LC50 in adult zebrafish was determined via an Acute Toxicity Study. ZnCl2 concentration for AD induction was determined via toxicity study and T-maze test. Finally, zebrafish were treated with ZnCl2 alone or simultaneously with either BBR or donepezil and assessed via the inhibitory avoidance task, followed by ELISA of AD-related biomarker levels in brain tissue. Results: The in silico assessment showed BBR’s desirable drug properties and binding affinity on selected AD-related targets, which was the greatest docking score with AChE. The in vitro IC50 on AChE was 3.45 μM. The LC50 in adult zebrafish was calculated at 366 ppm. In the T-maze test, ZnCl2 at 2.5 ppm caused the greatest cognitive impairment accompanied by moderate freezing. In the inhibitory avoidance test, fish treated with either 100 ppm BBR or 2.5 ppm donepezil had significantly better performance than ZnCl2-treated fish. ZnCl2-treated zebrafish brain tissue had the highest Aβ levels and AChE activity of all groups, but these were significantly lower in donepeziland BBR-treated fish. ZnCl2- and donepezil-treated fish had similar TNF-α levels, whereas BBR treatment significantly lowered them close to those of untreated fish. Conclusion: BBR showed anti-amyloidogenic, anti-AChE, and anti-inflammatory effects, which support its potential use in AD therapy.

Transcriptome and proteome profiling reveals TREM2-dependent and -independent glial response and metabolic perturbation in an Alzheimer’s mouse model

Elucidating the intricate molecular mechanisms of Alzheimer's disease (AD) requires a multidimensional analysis incorporating various omics data. In this study, we employed transcriptome and proteome profiling of AppNL-G-F, a human APP knock-in model of amyloidosis, at the early and mid-stages of amyloid-beta (Aβ) pathology to delineate the impacts of Aβ deposition on brain cells. By contrasting AppNL-G-F mice with TREM2 (Triggering receptor expressed on myeloid cells 2) knockout models, our study further investigates the role of TREM2, a well-known AD risk gene, in influencing microglial responses to Aβ pathology. Our results highlight altered microglial states as a central feature of Aβ pathology, characterized by the significant upregulation of microglia-specific genes related to immune responses such as complement system and antigen presentation, and catabolic pathways such as phagosome formation and lysosome biogenesis. The absence of TREM2 markedly diminishes the induction of these genes, impairs Aβ clearance, and exacerbates dystrophic neurite formation. Importantly, TREM2 is required for the microglial engagement with Aβ plaques and the formation of compact Aβ plaque cores. Furthermore, this study reveals substantial disruptions in energy metabolism and protein synthesis, signaling a shift from anabolism to catabolism in response to Aβ deposition. This metabolic alteration, coupled with a decrease in synaptic protein abundance, occurs independently of TREM2, suggesting the direct effects of Aβ deposition on synaptic integrity and plasticity. In summary, our findings demonstrate altered microglial states and metabolic disruption following Aβ deposition, offering mechanistic insights into Aβ pathology and highlighting the potential of targeting these pathways in AD therapy.

Joint administration of sub-threshold doses of the acetylcholinesterase inhibitor donepezil with those of the NMDA receptor antagonist ketamine improved rats’ recognition memory abilities

Alzheimer’s Disease (AD) is a serious progressive neurodegenerative illness conducting to the decay of cognitive functions. A few drugs have been approved for the therapy of AD, including the acetylcholinesterase inhibitors (AChEIs) like donepezil. Their efficiency, however, is modest and their application is associated with toxicity. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, a rapidly acting antidepressant, has been proposed as a potential agent for the treatment of AD. The present study was designed to investigate the effects exerted by the combination of sub-threshold doses of donepezil with those of ketamine on rats’ recognition memory abilities. For these experiments, the object recognition task (ORT) and the object location task (OLT), two procedures assessing non-spatial and spatial recognition memory respectively in rodents were used. Post-training acute administration of inactive doses of donepezil (0.3 mg/kg) and ketamine (1 mg/kg) counteracted non-spatial and spatial recognition memory impairments. The present findings, although preliminary, propose that the combined administration of ketamine and donepezil could represent a new strategy for the therapy of memory disorders, a common feature of AD patients.

Insulin-inspired hippocampal neuron–targeting technology for protein drug delivery

Hippocampal neurons can be the first to be impaired with neurodegenerative disorders, including Alzheimer's disease (AD). Most drug candidates for causal therapy of AD cannot either enter the brain or accumulate around hippocampal neurons. Here, we genetically engineered insulin-fusion proteins, called hippocampal neuron-targeting (Ht) proteins, for targeting protein drugs to hippocampal neurons because insulin tends to accumulate in the neuronal cell layers of the hippocampus. In vitro examinations clarified that insulin and Ht proteins were internalized into the cultured hippocampal neurons through insulin receptor-mediated macropinocytosis. Cysteines were key determinants of the delivery of Ht proteins to hippocampal neurons, and insulin B chain mutant was most potent in delivering cargo proteins. In vivo accumulation of Ht proteins to hippocampal neuronal layers occurred after intracerebroventricular administration. Thus, hippocampal neuron-targeting technology can provide great help for developing protein drugs against neurodegenerative disorders.

Mitochondria-targeting Cu2-xSe-TPP with dual enzyme activity alleviates Alzheimer's disease by modulating oxidative stress

Mitochondrial dysfunction in microglia has been implicated as a key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). Abnormal production of reactive oxygen species (ROS) and neuroinflammation caused by mitochondrial oxidative stress are important factors leading to neuronal death in AD. Herein, a "dual brake" strategy to synergistically halt mitochondrial dysfunction and neuroinflammation targeting mitochondria in microglia is proposed. To achieve this goal, (3-carboxypropyl) triphenyl-phosphonium bromide (TPP)-modified Cu2-xSe nanozymes (Cu2-xSe-TPP NPs) with dual enzyme-like activities was designed. Cu2-xSe-TPP NPs with superoxide dismutase-mimetic (SOD) and catalase-mimetic (CAT) activities can effectively scavenge ROS in the mitochondria of microglia and relieve mitochondrial oxidative stress. In vivo studies demonstrated that Cu2-xSe-TPP NPs can alleviate oxidative stress and promote neuroprotection in the hippocampus of AD model mice. In addition, Cu2-xSe-TPP NPs can regulate the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, promote Aβ phagocytosis and reshape the AD inflammatory microenvironment, thus effectively attenuating AD neuropathology and rescuing cognitive deficits in AD model mice. Taken together, this strategy preventing mitochondrial damage and remodeling the inflammatory microenvironment will provide a new perspective for AD therapy.

In Vivo Evaluation of Nose-to-Brain Delivery of Liposomal Donepezil, Memantine, and BACE-1 siRNA for Alzheimer's Disease Therapy.

Our study took an innovative approach by evaluating, in vivo, the efficacy of intranasal (IN) administration of liposomal formulations of donepezil, memantine, and beta-site amyloid precursor protein-cleaving enzyme (BACE-1) siRNA, and their combination as a "triple-drug therapy" in treating Alzheimer's disease (AD). Female APP/PS1 homozygous, transgenic mice were used as an AD model. The spatial short-term memory of the APP/PS1 mice was evaluated by a Y-maze behavioral test. IN-administered formulations demonstrated better short-term memory recovery than oral administration. Triple-drug therapy induced short-term memory recovery and lowered beta-amyloid (Aβ) 40 and 42 peptide levels and BACE-1 mRNA expression. Additionally, inflammatory cytokine mRNA expression was downregulated. This innovative approach opens new possibilities for Alzheimer's disease treatment and nose-to-brain delivery.

Phyto-nanotechnology: A novel beneficial strategy for Alzheimer's disease therapy

Alzheimer's disease, a neurodegenerative condition, is characterized by the slow and progressive deterioration of the cognitive functions of geriatric patients. It occurs due to exacerbation of neurons in the brain, indicated by loss of memory, mood instability, and even death. The aggregation of amyloid β protein and neurofibrillary tangles-atypical forms of tau protein is the major cause of this disease. Phytoconstituents have been frequently employed in treating Alzheimer's disease. These natural compounds act through different molecular mechanisms to treat the disease. However, their potential in Alzheimer's disease therapy may be limited due to poor blood-brain barrier permeability, off-target effects, low bioavailability, etc. In recent times, nanotechnology has gained attraction to overcome these challenges. This article focuses on the potential phytoconstituents for Alzheimer's disease treatment and the associated limitations. Moreover, it highlights various nanoformulation strategies employed to penetrate the blood-brain barrier effectively, avoid side effects, improve bioavailability, and target specificity in treating Alzheimer's disease. The integration of nanotechnology with plant-derived compounds has the potential to revolutionize the therapeutic landscape for Alzheimer's disease.

A medicine and food homology formula prevents cognitive deficits by inhibiting neuroinflammation and oxidative stress via activating AEA-Trpv1-Nrf2 pathway.

Alzheimer's disease (AD) is a neurodegenerative disorder frequently accompanied by neuroinflammation and oxidative stress. The medicine and food homology (MFH) has shown potential for treating neuroinflammation and oxidative stress. This study aimed to provide a safe and efficient therapy for AD based on MFH. In this study, we develop a MFH formula consisting of egg yolk oil, perilla seed oil, raphani seed oil, cinnamon oil, and noni puree (EPRCN). To evaluate the ameliorative effects of EPRCN on AD-related symptoms, a mouse model of AD was constructed using intraperitoneal injection of scopolamine in ICR mice. Experimental results demonstrated that EPRCN supplement restored behavioral deficits and suppressed neuroinflammation and oxidative stress in the hippocampus of scopolamine-induced mice. An in vitro study was then performed using induction of Aβ(25-35) in glial (BV-2 and SW-1783) and neuron (SH-SY5Y) cell lines to examine the improvement mechanism of EPRCN on cognitive deficits. Multi-omics and in vitro studies demonstrated that these changes were driven by the anandamide (AEA)-Trpv1-Nrf2 pathway, which was inhibited by AM404 (an AEA inhibitor), AMG9810 (a Trpv1 inhibitor), and BT (an Nrf2 inhibitor). Consequently, EPRCN is an effective therapy on preventing cognitive deficits in mouse models of AD. In contrast to donepezil, EPRCN exhibits a novel modes action for ameliorating neuroinflammation. The mechanism of EPRCN on preventing cognitive deficits is mediated by improving neuroinflammation and oxidative stress via activating the AEA-Trpv1-Nrf2 pathway.

The prion principle and Alzheimer's disease.

Similarities to molecular mechanisms underlying prion diseases may help to refine Alzheimer's disease therapies.

A Novel Tetrahydroacridine Derivative with Potent Acetylcholinesterase Inhibitory Properties and Dissociative Capability against Aβ42 Fibrils Confirmed by In Vitro Studies.

Alzheimer's disease (AD) is one of the most common causes of dementia, accounting for more than 60% of all cases. It is a neurodegenerative disease in which symptoms such as a decline in memory, thinking, learning, and organizing skills develop gradually over many years and eventually become more severe. To date, there is no effective treatment for the cause of Alzheimer's disease, and the existing pharmacological options primarily help manage symptoms. Treatment is mainly based on acetylcholinesterase (AChE) inhibitors such as donepezil, rivastigmine, and galantamine, which exhibit numerous adverse cardiovascular and gastrointestinal effects due to excessive stimulation of peripheral cholinergic activity involving muscarinic receptors. Therefore, in addition to the obvious drugs that act on the cause of the disease, new drugs based on AChE inhibition that show the fewest side effects are needed. One potential drug could be a new compound under study, tetrahydroacridine derivative (CHDA), which showed significant potential to inhibit the AChE enzyme in previous in vitro studies. The present study shows that while having very potent AChE inhibitory properties, CHDA is a compound with low toxicity to nerve cell culture and living organisms. In addition, it exhibits dissociative activity against amyloid β fibrils, which is extremely important for applications in Alzheimer's disease therapy.

Can Targeted Protein Degradation Technology Provide a Potential Breakthrough in the Development of Anti-AD Drugs?

Recent advancements in Alzheimer's disease (AD) research have led to the approval of lecanemab and donanemab, highlighting the effectiveness of amyloid-beta (Aβ) degradation as a treatment for AD. The prospect of small molecule Aβ degraders as a potential treatment, which utilizes emerging targeted protein degradation technology, is exciting, given their ability to address some of the limitations of current therapies and their promising future in AD treatment. Despite facing challenges, these degraders are poised to become a future treatment option, harnessing scientific breakthroughs for more targeted and effective AD therapy.

Hierarchical adhesive hydrogel microparticles with galantamine hydrobromide encapsulation for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is the most common type of dementia in aged individuals. Galantamine hydrobromide (GAH) is an approved medication for AD that has been shown to significantly enhance cognitive function, effectively manage behavioral symptoms, and improve performance in essential daily activities. However, the side effects of these drugs include nausea and vomiting, significant fluctuations in blood concentration, and poor patient compliance. Therefore, improving the route of administration and enhancing therapeutic efficacy are major research focuses. Here, we propose the use of hierarchically structured hydrogel-encapsulated mesoporous silica nanocarriers (MSNs) to encapsulate GAH, with the goal of minimizing adverse reactions in the stomach. By enabling the slow release of the drug over an extended period, these hydrogels aim to reduce the frequency of dosing, thereby improving the efficiency of drug administration and enhancing patient compliance. Owing to these properties, drug-carrying microcapsules are capable of achieving optimal drug delivery and have emerged as excellent candidates for AD therapy. We believe that this technology has the potential to significantly impact clinical treatment.

DVL/GSK3/ISL1 pathway signaling: unraveling the mechanism of SIRT3 in neurogenesis and AD therapy

BackgroundThe established association between Alzheimer's disease (AD) and compromised neural regeneration is well-documented. In addition to the mitigation of apoptosis in neural stem cells (NSCs), the induction of neurogenesis has been proposed as a promising therapeutic strategy for AD. Our previous research has demonstrated the effective inhibition of NSC injury induced by microglial activation through the repression of oxidative stress and mitochondrial dysfunction by Sirtuin 3 (SIRT3). Nonetheless, the precise role of SIRT3 in neurogenesis remains incompletely understood.MethodsIn vivo, SIRT3 overexpression adenovirus was firstly injected by brain stereotaxic localization to affect the hippocampal SIRT3 expression in APP/PS1 mice, and then behavioral experiments were performed to investigate the cognitive improvement of SIRT3 in APP/PS1 mice, as well as neurogenic changes in hippocampal region by immunohistochemistry and immunofluorescence. In vitro, under the transwell co-culture condition of microglia and neural stem cells, the mechanism of SIRT3 improving neurogenesis of neural stem cells through DVL/GSK3/ISL1 axis was investigated by immunoblotting, immunofluorescence and other experimental methods.ResultsOur findings indicate that the overexpression of SIRT3 in APP/PS1 mice led to enhanced cognitive function and increased neurogenesis. Additionally, SIRT3 was observed to promote the differentiation of NSCs into neurons during retinoic acid (RA)-induced NSC differentiation in vitro, suggesting a potential role in neurogenesis. Furthermore, we observed the activation of the Wnt/ß-catenin signaling pathway during this process, with Glycogen Synthase Kinase-3a (GSK3a) primarily governing NSC proliferation and GSK3ß predominantly regulating NSC differentiation. Moreover, the outcomes of our study demonstrate that SIRT3 exerts a protective effect against microglia-induced apoptosis in neural stem cells through its interaction with DVLs.ConclusionsOur results show that SIRT3 overexpressing APP/PS1 mice have improved cognition and neurogenesis, as well as improved neurogenesis of NSC in microglia and NSC transwell co-culture conditions through the DVL/GSK3/ISL1 axis.

Recent Advances of Mitochondrial Alterations in Alzheimer's Disease: A Perspective of Mitochondrial Basic Events.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders and is characterized by a decrease in learning capacity, memory loss and behavioral changes. In addition to the well-recognized amyloid-β cascade hypothesis and hyperphosphorylated Tau hypothesis, accumulating evidence has led to the proposal of the mitochondrial dysfunction hypothesis as the primary etiology of AD. However, the predominant molecular mechanisms underlying the development and progression of AD have not been fully elucidated. Mitochondrial dysfunction is not only considered an early event in AD pathogenesis but is also involved in the whole course of the disease, with numerous pathophysiological processes, including disordered energy metabolism, Ca2+ homeostasis dysfunction and hyperactive oxidative stress. In the current review, we have integrated emerging evidence to summarize the main mitochondrial alterations- bioenergetic metabolism, mitochondrial inheritance, mitobiogenesis, fission- fusion dynamics, mitochondrial degradation, and mitochondrial movement- underlying AD pathogenesis; precisely identified the mitochondrial regulators; discussed the potential mechanisms and primary processes; highlighted the leading players; and noted additional incidental signaling pathway changes. This review may help to stimulate research exploring mitochondrial metabolically-oriented neuroprotection strategies in AD therapies, leading to a better understanding of the link between the mitochondrial dysfunction hypothesis and AD pathogenesis.

Novel Therapeutic Approaches in Alzheimer's Disease

Alzheimer's disease (AD) is a neurological condition associated with a decrease in levels of acetylcholine and diminished cholinergic functions. This may be caused by the degeneration of cholinergic neurons in the brain, leading to cognitive deficits. Due to the difficulty and invasiveness of collecting cerebrospinal fluid (CSF) required for assessing conventional biomarkers, researchers are currently exploring less intrusive, less expensive, and more straightforward methods for diagnosing AD. Additionally, conventional interventions such as cholinesterase inhibitors like rivastigmine, donepezil, and galantamine are US FDA-approved drugs that are still effective for managing AD. The goal of this therapy is to increase acetylcholine levels in the brain by inhibiting the enzymes that degrade acetylcholine. Therefore, this therapeutic approach is useful for treating mild-to-moderate AD. However, only symptomatic treatment is currently available, and it can lead to serious adverse effects from conventional therapy. Thus, novel therapies for AD are needed in a growing global population. This manuscript provides information on various biomarkers with possible pathogenesis mechanisms, novel treatment strategies such as microalgae, HupA, cannabinoids, and the beneficial effects of coenzyme Q10, bacterial probiotics, omega-3 fatty acids, vitamin B12, and D3 in memory impairment for managing AD. Non-pharmacological treatments such as music therapy, Electroacupuncture (EA), or manual acupuncture (MA) also play an important role in enhancing the effectiveness of conventional pharmacological treatments for AD.

Membrane-assisted Aβ40 aggregation pathways.

Alzheimer's disease (AD) is caused by the assembly of amyloid-beta (Aβ) peptides into oligomers and fibrils. Endogenous Aβ aggregation may be assisted by cell membranes, which can accelerate the nucleation step enormously, but knowledge of membrane-assisted aggregation is still very limited. Here we used extensive MD simulations to structurally and energetically characterize key intermediates along the membrane-assisted aggregation pathways of Aβ40. Reinforcing experimental observations, the simulations reveal unique roles of GM1 ganglioside and cholesterol in stabilizing membrane-embedded β-sheets and of Y10 and K28 in the ordered release of a small oligomeric seed into solution. The same seed leads to either an open-shaped or R-shaped fibril, with significant stabilization provided by inter- or intra-subunit interfaces between a straight β-sheet (residues Q15-D23) and a bent β-sheet (residues A30-V36). This work presents the first comprehensive picture of membrane-assisted aggregation of Aβ40, with broad implications for developing AD therapies and rationalizing disease-specific polymorphisms of amyloidogenic proteins.

Research Progress of Novel Inorganic Nanomaterials in the Diagnosis and Treatment of Alzheimer's Disease.

The global increase in the number of Alzheimer's disease (AD) patients has posed numerous treatment challenges. Six Food and Drug Administration-approved medications (e.g., donepezil and memantine) have demonstrated some efficacy but are primarily used to alleviate symptoms. The etiology of AD is unknown, and the blood-brain barrier restricts drug penetration, which severely restricts the use of various therapeutic agents. With their high targeting, long-lasting effect, and multifunctionality, inorganic nanomaterials provide a novel approach to the treatment of AD. A review of inorganic nanoparticles in the diagnosis and therapy of AD. This paper reviews the research literature on the use of inorganic nanomaterials in the treatment of AD. Gold nanoparticles, superparamagnetic iron oxide nanoparticles, magnetic nanoparticles, carbon nanotubes, and quantum dots are among the inorganic nanomaterials studied. As knowledge of the origins of AD remains limited, the majority of studies on inorganic nanomaterials have primarily focused on interventions on Aβ proteins. Adjusting and enhancing the properties of these inorganic nanomaterials, such as core-shell structure design and surface modification, confer benefits for the treatment of AD. Inorganic nanoparticles have a wide spectrum of therapeutic potential for AD. Despite their potential benefits, however, the safety and translation of inorganic nanomaterials into clinical applications remain formidable obstacles.

Targeting ceramide-induced microglial pyroptosis: Icariin is a promising therapeutic therapy for Alzheimer's disease

Alzheimer’s disease (AD), a progressive dementia, is one of the most common neurodegenerative diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Herein, we spotlight the dysregulation of lipid metabolism, particularly the elevation of ceramides (Cers), as a critical yet underexplored facet of AD pathogenesis. Our study delineates the role of Cers in promoting microglial pyroptosis, a form of programmed cell death distinct from apoptosis and necroptosis, characterized by cellular swelling, and membrane rupture mediated by the NLRP3 inflammasome pathway. Utilizing both in vivo experiments with APP/PS1 transgenic mice and in vitro assays with BV-2 microglial cells, we investigate the activation of microglial pyroptosis by Cers and its inhibition by Icariin (ICA), a flavonoid with known antioxidant and anti-inflammatory properties. Our findings reveal a significant increase in Cers levels and pyroptosis markers (NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, gasdermin D, and interleukin-18) in the brains of AD model mice, indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis. Conversely, ICA treatment effectively reduces these pyroptotic markers and Cer levels, thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD. This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy, capable of mitigating neuroinflammation and pyroptosis through the COX2-NLRP3 inflammasome-GSDMD axis. Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.