Animal Models Of Alzheimer's Disease Research Articles

Intermittent fasting and neurocognitive disorders: What the evidence shows.

Intermittent fasting (IF) has emerged as a potential lifestyle intervention for mitigating cognitive decline and enhancing brain health in individuals with mild to major neurocognitive disorders. Unlike preventive strategies, this review evaluates IF as a therapeutic approach, focusing on its effects on neuroplasticity, inflammation, and cognitive function. A narrative review was conducted using a comprehensive PubMed search with the terms "intermittent fasting AND neurocognition" and "intermittent fasting AND neuroplasticity". Studies published in English within the last ten years involving human and animal models were included. Exclusion criteria focused on studies primarily examining mood disorders or unrelated metabolic outcomes. Preclinical evidence demonstrates that IF enhances hippocampal neurogenesis and synaptic plasticity through pathways involving BDNF and CREB. IF also reduces neuroinflammation, as shown in animal models of Alzheimer's disease, vascular cognitive impairment, and high-fat diet-induced cognitive impairment. Human studies, though limited, suggest that regular IF may improve cognitive function and reduce markers of oxidative stress and inflammation in individuals with mild cognitive impairment. Current findings highlight the therapeutic potential of IF for individuals with existing cognitive impairment. While preclinical studies provide robust evidence of neuroprotective mechanisms, human studies remain sparse and require standardization. Further clinical research is necessary to confirm long-term safety and efficacy and to refine IF protocols for broader clinical application.

Intranasal amyloid model of Alzheimer's disease - potential opportunities and challenges.

Amyloid beta 1-42 (Aβ1-42) peptide is one of the most studied disease-related amyloidogenic peptides implicated in the pathophysiology of Alzheimer's disease (AD). Despite significant scientific breakthroughs in the recent past, the existing non-transgenic animal models do not demonstrate accurate pathology of AD progression. This review has presented a concise mechanistic understanding of the intranasal amyloid-based animal model of AD, along with its advantages, challenges, and major limitations. Furthermore, discussions on how to combat these challenges to pave the road toward developing novel therapeutics for AD, have also been included. Preclinical exploration of repeated intranasal amyloid-beta exposure would certainly aid the translational development of a robust animal model of AD. This will also provide a better understanding of disease progression and pathology in the intranasal animal model.

PDE4D inhibitors: Opening a new era of PET diagnostics for Alzheimer's disease.

As the incidence of Alzheimer's disease (AD) continues to rise, the need for an effective PET radiotracer to facilitate early diagnosis has become more pressing than ever before in modern medicine. Phosphodiesterase (PDE) is closely related to cognitive impairment and neuroinflammatory processes in AD. Current research progress shows that specific PDE4D inhibitors radioligands can bind specifically to the PDE4D enzyme in the brain, thereby showing pathology-related signal enhancement in AD animal models, indicating the potential of these ligands as effective radiotracers. At the same time, we need to pay attention to the important role computer aided drug design (CADD) plays in advancing AD drug design and PET imaging. Future research will verify the potential of these ligands in clinical applications through computer simulation techniques, providing patients with timely intervention and treatment, which is of great significance.

Dimethysiloxane polymer for the effective transdermal delivery of donepezil in Alzheimer's disease treatment.

Donepezil (DNZ) has been used to treat dementia associated with mild, moderate, or severe Alzheimer's disease (AD). DNZ uptake can alleviate cognitive symptoms in AD patients via acetylcholinesterase (AChE) inhibition. However, oral administration of DNZ has limitations, including first-pass metabolism, difficulties with swallowing, and low patient compliance. In this work, we disclose a novel transdermal DNZ delivery system utilizing T2 polymer, synthesized via the ring-opening polymerization of 2,2,5,5-tetramethyl-2,5-disila-1-oxacyclopentane with trifluoroacetic acid (TFA). In the in vivo studies in an AD animal model, the DNZ-loaded T2 polymer (DNZ@T2) facilitated efficient transdermal DNZ delivery to the bloodstream and improved spatial working memory and long-term memory of the AD mouse model. Both the T2 polymer and DNZ@T2 exhibited low cytotoxicity and non-significant in vivo toxicity. This research highlights a promising transdermal delivery strategy for AD treatment, potentially enhancing therapeutic efficacy and patient compliance.

Efficacy and Safety of Natural Apigenin Treatment for Alzheimer's Disease: Focus on In vivo Research Advancements.

Alzheimer's Disease (AD) is the most common dementia in clinics. Despite decades of progress in the study of the pathogenesis of AD, clinical treatment strategies for AD remain lacking. Apigenin, a natural flavonoid compound, is present in a variety of food and Chinese herbs and has been proposed to have a wide range of therapeutic effects on dementia. To clarify the relevant pharmacological mechanism and therapeutic effect of apigenin on animal models of AD. Computer-based searches of the PubMed, Cochrane Library, Embase, and Web of Science databases were used to identify preclinical literature on the use of apigenin for treating AD. All databases were searched from their respective inception dates until June 2023. The meta-analysis was performed with Review manager 5.4.1 and STATA 17.0. Thirteen studies were eventually enrolled, which included 736 animals in total. Meta-analysis showed that apigenin had a positive effect on AD. Compared to controls, apigenin treatment reduced escape latency, increased the percentage of time spent in the target quadrant and the number of plateaus traversed; apigenin was effective in reducing nuclear factor kappa-B (NF-κB) p65 levels; apigenin effectively increased antioxidant molecules SOD and GSH-px and decreased oxidative index MDA; for ERK/CREB/BDNF pathway, apigenin effectively increased BDNF and pCREB molecules; additionally, apigenin effectively decreased caspase3 levels and the number of apoptotic cells in the hippocampus. The results show some efficacy of apigenin in the treatment of AD models. However, further clinical studies are needed to confirm the clinical efficacy of apigenin.

High‐frequency oscillations in animal models of Alzheimer’s Disease

High‐frequency oscillations in animal models of Alzheimer’s Disease

Microglial‐targeted nSMase2 inhibitor fails to reduce tau spread in the animal model of Alzheimer’s disease

Microglial‐targeted nSMase2 inhibitor fails to reduce tau spread in the animal model of Alzheimer’s disease

A randomized clinical trial evaluating Hydralazine’s efficacy in early-stage Alzheimer’s disease: The EHSAN Study

Alzheimer’s Disease (AD), a neurodegenerative disorder escalating worldwide, remains incurable with existing interventions merely mitigating symptoms. Hydralazine, an antihypertensive agent, has displayed neuroprotective potential in AD animal models via amplification of mitochondrial functionality and stimulation of stress management and repair pathways. Nevertheless, its effectiveness and tolerability in human AD cohorts are yet to be confirmed. This study protocol describes the design of an ongoing, single-center, randomized, triple-blind, placebo-controlled trial to assess hydralazine’s effects on cognitive function in mild to moderate -stage AD patients. We will enroll 424 patients aged 50 and older, meeting NINCDS-ADRDA criteria for probable AD with Mini-Mental State Examination scores from 12–26. They’ll be randomly assigned to receive either hydralazine HCL (25 mg, thrice daily) or a placebo for 12 months. The primary outcome is the Alzheimer’s Disease Assessment Scale change from baseline to 12 months. Secondary outcomes include various measures using Lawton instrumental activities of daily living scale, neuropsychiatry inventory, and caregiver activity survey. This trial will explore the potential benefits and risks of hydralazine in mild to moderate AD treatment. It’s the first trial examining hydralazine’s impact on mild to moderate -stage AD in human and is registered at the Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552AQ, registered 13/04/2021). Ethics approval was granted by the Research Ethics Committee of the National Institute for Medical Research Development (IR.NIMAD.REC.1398.424), following the SPIRIT Statement guidelines. Findings will be disseminated via peer-reviewed publications and conferences. This inaugural human clinical trial evaluates hydralazine’s impact on patients in the mild to moderate AD. Executed with a randomized, triple-blind, placebo-controlled methodology, this study incorporates a significant sample size and an extended monitoring duration. Multiple parameters, including cognitive capabilities, will be assessed. Potential limitations include the inherent homogeneity of the AD cohort, the lack of biomarker assays, and the unpredictable progression of the disease. Notably, the study might not elucidate the protracted effects of hydralazine beyond a 12-month period. Another limitation of our clinical trial is that patients were diagnosed with Alzheimer’s disease based solely on clinical evaluation and MRI findings, without the inclusion of specific biomarkers, which may impact the accuracy and specificity of the diagnosis. Trial registration: Iranian Registry of Clinical Trials (IRCT20200711048075N1, registered 29/07/2020) and ClinicalTrials.gov (NCT 04,842,552, registered 13/04/2021).

Comparative Study of Injected Alzheimer's Disease Models in Rats: Insights from Experimental Research.

Alzheimer's disease (AD) remains incurable, highlighting the need for new and diverse animal models to better understand its complex mechanisms. This study compares various injected animal models of AD, focusing on the main theories that explain the disease; Methods: Female Wistar rats (10-months old) were administered intracebroventricularly by artificial cerebrospinal fluid (aCSF) (Control), beta amyloid Aβ1-42 (BA), okadaic acid (OKA), lipopolysaccharides (LPS), buthionine sulfoximine (BSO) or by a mixture of these different molecules (MLG). Cognitive performance was assessed one week or one month after stereotaxic surgery; Results: Our results, show that only the Aβ and the MLG induced a persistence and progressive deficits in the working memory, recognition memory and spatial memory in rats. As the hippocampus (HIP) and the prefrontal cortex (PFC) are particularly involved in memory behavior, we analyzed long-term neuroadaptations in these brain subregions using spectrophotometric and histological methods to assess oxidative stress changes and neuronal loss, respectively. We found that the behavioral impairments in memory and learning were accompanied by irreversible oxidative stress changes and neurodegenerescence, particularly in the HIP; Conclusions: This study provides promising data on the modeling of AD in order to develop an effective therapeutic approach.

Therapeutic efficacy of amygdaline and amygdaline-loaded niosomes in a rat model of Alzheimer’s disease via oxidative stress, brain neurotransmitters, and apoptotic pathway

Abstract Background Alzheimer’s disease (AD) is a specific form of neurodegeneration that is marked by impairments in memory and cognition. Exposure to some metal toxins, such as aluminum (AL), was directly linked to the onset of AD as it was hosted in the body via several exposure routes and can change the permeability and cross the blood–brain barrier. Due to amygdaline’s existence, apricot kernel therapy for AD is believed to have been established to be successful in numerous investigations. Amygdaline has been shown to have antioxidant effects that mitigate oxidative damage, and free radicals scavenger activity, as well as amygdaline niosomes as a nanoparticle has been found to improve the drug’s efficiency and selectivity. The objectives of this investigation are to study the neuroprotective role of amygdaline, and amygdaline-loaded niosomes formulation in the diminishment of the incidence of AD in neurotoxin (aluminum chloride; AlCl3) AD animal model. Results Data revealed that AlCl3 caused cognitive decline that was confirmed by cognitive behavioral tests (novel object and Y-maze); biochemical disturbances that include marked oxidative stress (elevated malondialdehyde and reduced total antioxidant capacity), reduced acetylcholinesterase, and brain monoamines levels (nor adrenalin; 4-dihydroxyphenylacetic acid; 5-hydroxytryptamine /serotonin; dopamine), and gene regulation upset (down-regulated transcript levels of acetylcholinesterase; monoamine oxidase; BCL-2 and up-regulated transcript levels of BAX), as well as neurodegenerative changes were observed in the hippocampus of AlCl3-treated rats. Treatment with amygdaline and amygdaline-loaded niosomes formulation improved working memory and recognition, alleviated oxidative stress, and restored the levels of brain monoamines and neurotransmitters. Moreover, gene expression data showed a significant down-regulation of BAX, while BCL-2, acetylcholinesterase, and monoamine oxidase were significantly up-regulated. Additionally, the histopathological examination showed reduced neurodegeneration. Conclusion Conclusively, it was evident that amygdaline and amygdaline-loaded niosomes formulation possess a neuroprotective and cognitive enhancement role in AD via their potent antioxidant potential, neurotransmitters, and gene expression regulations, as well as neural damage reduction capability. Graphical abstract

FAAH Inhibition Counteracts Neuroinflammation via Autophagy Recovery in AD Models.

Endocannabinoids have attracted great interest for their ability to counteract the neuroinflammation underlying Alzheimer's disease (AD). Our study aimed at evaluating whether this activity was also due to a rebalance of autophagic mechanisms in cellular and animal models of AD. We supplied URB597, an inhibitor of Fatty-Acid Amide Hydrolase (FAAH), the degradation enzyme of anandamide, to microglial cultures treated with Aβ25-35, and to Tg2576 transgenic mice, thus increasing the endocannabinoid tone. The addition of URB597 did not alter cell viability and induced microglia polarization toward an anti-inflammatory phenotype, as shown by the modulation of pro- and anti-inflammatory cytokines, as well as M1 and M2 markers; moreover microglia, after URB597 treatment released higher levels of Bdnf and Nrf2, confirming the protective role underlying endocannabinoids increase, as shown by RT-PCR and immunofluorescence experiments. We assessed the number and area of amyloid plaques in animals administered with URB597 compared to untreated animals and the expression of autophagy key markers in the hippocampus and prefrontal cortex from both groups of mice, via immunohistochemistry and ELISA. After URB597 supply, we detected a reduction in the number and areas of amyloid plaques, as detected by Congo Red staining and a reshaping of microglia activation as shown by M1 and M2 markers' modulation. URB597 administration restored autophagy in Tg2576 mice via an increase in BECN1 (Beclin1), ATG7 (Autophagy Related 7), LC3 (light chain 3) and SQSTM1/p62 (sequestrome 1) as well as via the activation of the ULK1 (Unc-51 Like Autophagy Activating Kinase 1) signaling pathway, suggesting that it targets mTOR/ULK1-dependent autophagy pathway. The potential of endocannabinoids to rebalance autophagy machinery may be considered as a new perspective for therapeutic intervention in AD.

Protective Activity of Melatonin Combinations and Melatonin-Based Hybrid Molecules in Neurodegenerative Diseases.

The identification of protective agents for the treatment of neurodegenerative diseases is the mainstay therapeutic goal to modify the disease course and arrest the irreversible disability progression. Pharmacological therapies synergistically targeting multiple pathogenic pathways, including oxidative stress, mitochondrial dysfunction, and inflammation, are prime candidates for neuroprotection. Combination or synergistic therapy with melatonin, whose decline correlates with altered sleep/wake cycle and impaired glymphatic "waste clearance" system in neurodegenerative diseases, has a great therapeutic potential to treat inflammatory neurodegenerative states. Despite the protective outcomes observed in preclinical studies, mild or poor outcomes were observed in clinical settings, suggesting that melatonin combinations promoting synergistic actions at appropriate doses might be more suitable to treat multifactorial neurodegenerative disorders. In this review, we first summarize the key melatonin actions and pathways contributing to cell protection and its therapeutic implication in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We remark the major controversies in the field, mostly generated by the lack of a common consensus for the optimal dosing, molecular targets, and toxicity. Then, we review the literature investigating the efficacy of melatonin combinations with approved or investigational neuroprotective agents and of melatonin-containing hybrid molecules, both in vitro and in animal models of AD, PD, and MS, as well as the efficacy of add-on melatonin in clinical settings. We highlight the rationale for such melatonin combinations with a focus on the comparison with single-agent treatment and on the assays in which an additive or a synergistic effect has been achieved. We conclude that a better characterization of the mechanisms underlying such melatonin synergistic actions under neuroinflammation at appropriate doses needs to be tackled to advance successful clinical translation of neuroprotective melatonin combination therapies or melatonin-based hybrid molecules.

Recombinant Antibody Fragments for Neurological Disorders: An Update.

Recombinant antibody fragments are promising alternatives to full-length immunoglobulins, creating big opportunities for the pharmaceutical industry. Nowadays, antibody fragments such as antigen-binding fragments (Fab), single-chain fragment variable (scFv), single-domain antibodies (sdAbs), and bispecific antibodies (bsAbs) are being evaluated as diagnostics or therapeutics in preclinical models and in clinical trials. Immunotherapy approaches, including passive transfer of protective antibodies, have shown therapeutic efficacy in several animal models of Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Huntington's disease (HD), transmissible spongiform encephalopathies (TSEs) and multiple sclerosis (MS). There are various antibodies approved by the Food and Drug Administration (FDA) for treating multiple sclerosis and two amyloid beta-specific humanized antibodies, Aducanumab and Lecanemab, for AD. Our previous review summarized data on recombinant antibodies evaluated in pre-clinical models for immunotherapy of neurodegenerative diseases. Here, we explore recent studies in this fascinating research field, give an update on new preventive and therapeutic applications of recombinant antibody fragments for neurological disorders and discuss the potential of antibody fragments for developing novel approaches for crossing the blood-brain barrier (BBB) and targeting cells and molecules of interest in the brain.

A Biocompatible Hydrogen-Bonded Organic Framework (HOF) as Sonosensitizer and Artificial Enzyme for In-Depth Treatment of Alzheimer's Disease.

Current phototherapeutic approaches for Alzheimer's disease (AD) exhibit restricted clinical outcomes due to the limited physical penetration and comprised brain microenvironment of noninvasive nanomedicine. Herein, a hydrogen-bonded organic framework (HOF) based sonosensitizer is designed and synthesized. Mn-TCPP, a planar molecule where Mn2+ ion is chelated in the core with a large p-conjugated system and 4 carboxylate acid groups, has been successfully used as building blocks to construct an ultrasound-sensitive HOF (USI-MHOF), which can go deep in the brain of AD animal models. The both in vitro and in vivo studies indicate that USI-MHOF can generate singlet oxygen (1O2) and oxidize β-amyloid (Aβ) to inhibit aggregation, consequently attenuating Aβ neurotoxicity. More intriguingly, USI-MHOF exhibits catalase (CAT)- and superoxide dismutase (SOD)-like activities, mitigating neuron oxidative stress and reprograming the brain microenvironment. For better crossing the blood-brain barrier (BBB), the peptide KLVFFAED (KD8) has been covalently grafted to USI-MHOF for improving BBB permeability and Aβ selectivity. Further, in vivo experiments demonstrate a significant reduction of the craniocerebral Aβ plaques and improvement of the cognition deficits in triple-transgenic AD (3×Tg-AD) mice models following deep-penetration ultrasound treatment. The work provides the first example of an ultrasound-responsive biocompatible HOF as non-invasive nanomedicine for in-depth treatment of AD.

Deficiency of NLRP3 protects cerebral pericytes and attenuates Alzheimer's pathology in tau-transgenic mice.

Activation of NLRP3-containing inflammasome, which is responsible for IL-1β maturation, has been shown to contribute to Alzheimer's disease (AD)-associated pathogenesis in both APP- and tau-transgenic mice. However, effects of NLRP3 on pericytes and subsequent cerebrovascular pathology in AD remain unknown. NLRP3-deficient and wild-type AD animal models were generated by crossing human P301S tau-transgenic mice and Nlrp3 knockout mice. AD-associated neuroinflammation, tauopathy, vasculature and pericyte coverage in the brain were investigated using immunohistological and molecular biological methods. To investigate how NLRP3 regulates pericyte activation and survival, pericytes from the brains of Nlrp3 knockout and wild-type mice were cultured, treated with IL-1β and H2O2 at different concentrations and analyzed by confocal microscopy and flow cytometry after staining with fluorescently labelled phalloidin, annexin-V and PDGFRβ antibody. Deficiency of NLRP3 (1) reduced Iba-1, GFAP and AT8 antibody-immunoreactive phosphorylated tau-positive cells, without significantly altering transcription of inflammatory genes, (2) preserved cerebral vasculature and pericyte coverage and up-regulated Osteopontin gene transcription, and (3) improved cognitive function in tau-transgenic mice. In cell culture, NLRP3 deficiency prevented pericyte apoptosis. Treatment with IL-1β or H2O2 increased the expression of PDGFRβ in NLRP3-deficient pericytes, but decreased it in NLRP3 wild-type pericytes in a dose-dependent manner. Inhibition of NLRP3 can promote pericyte survival, improve cerebrovascular function, and attenuate AD pathology in the brain of tau-transgenic mice. Our study supports NLRP3 as a novel therapeutic target for Alzheimer's patients.

Virus-like Particles-Based Vaccine to Combat Neurodegenerative Diseases.

Neurodegenerative diseases are regarded as gradual, incurable conditions with an insidious onset. Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most prevalent neurodegenerative diseases reported globally. Developing effective treatment strategies for neurodegenerative diseases has remained a primary objective and a huge challenge for researchers. The therapeutic medications that are now approved for the treatment of neurodegenerative diseases merely treat the symptoms; the underlying pathology is not addressed. Therefore, the emergence of novel disease-modifying therapeutic modalities such as immunotherapy has opened a new path in developing effective treatments for neurogenerative diseases. Compared to other types of subunit active vaccines, virus-like particles (VLPs) are considerably more immunogenic as they present dense and repetitive viral antigen epitopes on their surface, which can trigger both humoral and cell-mediated immune responses. They are also a much safer option than the traditional inactivated and live-attenuated vaccines since they are devoid of viral genomes and are, therefore, non-pathogenic and non-infectious. Researchers have turned their attention to VLPs as an active immunotherapy candidate for AD due to the lessons learned from the AN1792 trial. Studies have shown that they effectively induce anti-Aβ, anti-tau, and anti-α-Synuclein antibodies while avoiding T-cell-related immune reactions in animal models of AD and PD. This review compiles the findings of preclinical animal model studies and clinical investigations on VLP-based vaccines for neurogenerative diseases thus far. The technical limitations and potential difficulties associated with the future application of VLP-based vaccines in patients with neurodegenerative diseases have also been covered.

Effects of Artemisia asiatica ex on Akkermansia muciniphila dominance for modulation of Alzheimer's disease in mice.

The gut microbiome influences neurological disorders through bidirectional communication between the gut and the brain, i.e., the gut-brain axis. Artemisia asiatica ex, an extract of Artemisia asiatica Nakai (Stillen®, DA-9601) has been reported to improve depression by increasing brain-derived neurotropic factor. Therefore, we hypothesized that DA-9601 can be a potential therapeutic candidate for Alzheimer's disease (AD) acting through the gut-brain axis. Four groups of Tg2576 mice were used as the animal model for AD: wild type mice (n = 6), AD mice (n = 6), and DA-9601-administered AD mice given dosages of 30mg/kg/day (DA_30mg; n = 6) or 100mg/kg/day (DA_100mg; n = 6). Microglial activation, blood‒brain barrier integrity, amyloid beta accumulation, cognitive behavior, and changes in the gut microbiome were analyzed. DA-9601 improved the cognitive behavior of mice (DA_30mg **p<0.01; DA_100mg **p<0.01) and reduced amyloid beta accumulation (DA_30mg ***p<0.001; DA_100mg **p<0.01). Increased Iba-1 and upregulation of claudin-5 (DA_30mg *p<0.05) and occludin (DA_30mg **p<0.01; DA_100mg ***p<0.001) indicated altered microglial activation and improved blood‒brain barrier integrity. Akkermansia muciniphila was dramatically increased by DA-9601 administration (DA_30mg 47%; DA_100mg 61%). DA-9601 improved AD pathology with Akkermansia muciniphila dominance in the gut microbiome in a mouse model of AD, inferring that DA-9601 can affect AD through the gut-brain axis.

Huang-Pu-Tong-Qiao Formula Alleviates Hippocampal Neuron Damage by Inhibiting NLRP3 Inflammasome-mediated Pyroptosis in Alzheimer's Disease.

Huang-Pu-Tong-Qiao (HPTQ), a Traditional Chinese Medicine formula, has achieved remarkable efficacy in clinically treating Alzheimer's disease (AD). Pyroptosis refers to the inflammatory necrosis of cells, which contributes to AD pathological progression. However, it is unclear whether the therapeutic effect of HPTQ on AD is related to reducing pyroptosis. In this study, the network pharmacology analysis was used to predict the molecular mechanism of HPTQ in treating AD and validated our hypothesis through mice and cell experiments. APP/PS1 transgenic mice and Aβ25-35-injured HT22 cells were used as AD models in vivo and in vitro. The pharmacological effects and mechanisms of HPTQ on AD were evaluated by Morris water maze, Y-maze, transmission electron microscope, immunofluorescence, Hoechst/PI staining, western blot, and ELISA. Network pharmacology reveals the correlation between the therapeutic effect of HPTQ on AD and the NOD-like receptor signaling pathway. In APP/PS1 mice, HPTQ reduced the escape latency and maintained cell membrane integrity. In HT22 cells, 15% HPTQ-medicated serum and 10 µM MCC950 increased cell viability and decreased PI positive rate compared with the Model group. In addition, HPTQ treatment in AD animal and cell models reduced the protein expressions of NLRP3, ASC, cleaved caspase-1, GSDMD, GSDMD-N, IL-1β, and IL-18. The experimental results of MCC950 specifically inhibiting the NLRP3 expression suggested that HPTQ might reduce neuronal pyroptosis by reducing NLRP3 inflammasome. Network pharmacology and experimental validation suggested that HPTQ alleviated NLRP3 inflammasome-mediated neuronal pyroptosis in AD, which could provide valuable candidate drugs for AD clinical treatment.

Effects of Epothilone D on Social Defeat Stress-induced Changes in Microtubule-related and Endoplasmic Reticulum Stress Protein Expression.

Epothilone D (EpoD), microtubule (MT) stabilizing agent, demonstrated promising results in the animal models of Alzheimer's disease, Parkinson's disease and schizophrenia. The present study sought to investigate preventive effects of EpoD on altered changes of MT related proteins and endoplasmic reticulum (ER) stress proteins induced by social defeat stress (SDS). We measured protein expression levels of α-tubulin and its post-translational modifications, MT-associated protein 2, stathmin1 and 2 with their phosphorylated forms, and ER stress markers, 78-kDa glucose-regulated protein (GRP-78) and CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) in the prefrontal cortex (PFC) and hippocampus (HIP) of C57BL/6J strain mice treated with EpoD (2 mg/kg) or its vehicle, dimethylsulfoxide (DMSO), and exposed to SDS. We observed lower levels of acetylated α-tubulin, MAP2, p-STMN (Ser16), and GRP-78 in the PFC of the EpoD-Con group when compared to the DMSO-Con group. On the other hand, in the HIP, there were significantly higher levels of tyrosinated α-tubulin and GRP-78 in the EpoD-Defeat group compared to the DMSO-Defeat group. Furthermore, the level of MAP2 in the HIP was found to be lower in the EpoD-Con group compared to the DMSO-Con group. Our results suggest that EpoD exhibits a dual impact, manifesting both beneficial and detrimental effects on the aberrant changes of MT-related proteins and ER stress proteins induced by SDS, depending on the brain regions. These findings underscore the complexity of EpoD's effects, necessitating further exploration to understand its intricate mechanisms in cellular pathways linked to SDS.

Leucettinib-21, a DYRK1A Kinase Inhibitor as Clinical Drug Candidate for Alzheimer's Disease and Down Syndrome.

Alzheimer's disease (AD) and Down syndrome (DS) share a common therapeutic target, the dual-specificity, tyrosine phosphorylation activated kinase 1A (DYRK1A). Abnormally active DYRK1A is responsible for cognitive disorders (memory, learning, spatial localization) observed in both conditions. In DS, DYRK1A is overexpressed due to the presence of the DYRK1A gene on chromosome 21. In AD, calcium-activated calpains cleave full-length DYRK1A (FL-DYRK1A) into a more stable and more active, low molecular weight, kinase (LMW-DYRK1A). Genetic and pharmacological experiments carried out with animal models of AD and DS strongly support the idea that pharmacological inhibitors of DYRK1A might be able to correct memory/learning disorders in people with AD and DS. Starting from a marine sponge natural product, Leucettamine B, Perha Pharmaceuticals has optimized, through classical medicinal chemistry, and extensively characterized a small molecule drug candidate, Leucettinib-21. Regulatory preclinical safety studies in rats and minipigs have been completed and formulation of Leucettinib-21 has been optimized as immediate-release tablets. Leucettinib-21 is now undergoing a phase 1 clinical trial (120 participants, including 12 adults with DS and 12 patients with AD). The therapeutic potential of DYRK1A inhibitors in AD and DS is presented.