J Comput Chem. 2025 Jan 15;46(2):e70029. doi: 10.1002/jcc.70029.

ABSTRACT

Phosphodiesterase 5 (PDE5) inhibitors have shown great potential in treating Alzheimer's disease by improving memory and cognitive function. In this study, we evaluated fluspirilene, a drug commonly used to treat schizophrenia, as a potential PDE5 inhibitor using computational methods. Molecular docking revealed that fluspirilene binds strongly to PDE5, supported by hydrophobic and aromatic interactions. Molecular dynamics simulations confirmed that the fluspirilene-PDE5 complex is stable and maintains its structural integrity over time. Binding energy calculations further highlighted favorable interactions, indicating that the drug forms a strong and stable bond with PDE5. Additional analyses, including studies of protein dynamics and energy landscape mapping, revealed how the drug interacts dynamically with PDE5, adapting to different conformations and maintaining stability. These findings suggest that fluspirilene may modulate PDE5 activity, potentially offering therapeutic benefits for Alzheimer's disease. This study provides strong evidence for repurposing fluspirilene as a treatment for Alzheimer's and lays the foundation for further experimental and clinical investigations.

PMID:39797567 | DOI:10.1002/jcc.70029

Cancers (Basel). 2025 Jan 3;17(1):132. doi: 10.3390/cancers17010132.

ABSTRACT

BACKGROUND/OBJECTIVES: Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with a rising global incidence and poor prognosis, largely due to late-stage diagnosis and limited effective treatment options. Standard chemotherapy regimens, including cisplatin and gemcitabine, often fail because of the development of multidrug resistance (MDR), leaving patients with few alternative therapies. Doxycycline, a tetracycline antibiotic, has demonstrated antitumor effects across various cancers, influencing cancer cell viability, apoptosis, and stemness. Based on these properties, we investigated the potential of doxycycline to overcome gemcitabine resistance in iCCA.

METHODS: We evaluated the efficacy of doxycycline in two MDR iCCA cell lines, MT-CHC01R1.5 and 82.3, assessing cell cycle perturbation, apoptosis induction, and stem cell compartment impairment. We assessed the in vivo efficacy of combining doxycycline and gemcitabine in mouse xenograft models.

RESULTS: Treatment with doxycycline in both cell lines resulted in a significant reduction in cell viability (IC50 ~15 µg/mL) and induction of apoptosis. Doxycycline also diminished the cancer stem cell population, as indicated by reduced cholangiosphere formation. In vivo studies showed that while neither doxycycline nor gemcitabine alone significantly reduced tumor growth, their combination led to marked decreases in tumor volume and weight at the study endpoint. Additionally, metabolic analysis revealed that doxycycline reduced glucose uptake in tumors, both as a monotherapy and more effectively in combination with gemcitabine.

CONCLUSIONS: These findings suggest that doxycycline, especially in combination with gemcitabine, can restore chemotherapy sensitivity in MDR iCCA, providing a promising new strategy for improving outcomes in this challenging disease.

PMID:39796759 | DOI:10.3390/cancers17010132

Foods. 2025 Jan 2;14(1):102. doi: 10.3390/foods14010102.

ABSTRACT

Oncostatin M (OSM) plays a crucial role in diverse inflammatory reactions. Although the food bioactive compound naringenin (NAR) exerts various useful effects, including antitussive, anti-inflammatory, hepatoprotective, renoprotective, antiarthritic, antitumor, antioxidant, neuroprotective, antidepressant, antinociceptive, antiatherosclerotic, and antidiabetic effects, the modulatory mechanism of NAR on OSM expression in neutrophils has not been specifically reported. In the current work, we studied whether NAR modulates OSM release in neutrophil-like differentiated (d)HL-60 cells. To assess the modulatory effect of NAR, enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunofluorescence assay were employed. While exposure to granulocyte-macrophage colony-stimulating factor (GM-CSF) induced elevated OSM release and mRNA expression, the elevated OSM release and mRNA expression were diminished by the addition of NAR in dHL-60 cells. While the phosphorylation of phosphatidylinositol 3-kinase, protein kinase B (Akt), and nuclear factor (NF)-κB was upregulated by exposure to GM-CSF, the upregulated phosphorylation was inhibited by the addition of NAR in dHL-60 cells. Consequently, the results indicate that the food bioactive compound NAR may have a positive effect on health (in health promotion and improvement) or may play a role in the prevention of inflammatory diseases.

PMID:39796391 | DOI:10.3390/foods14010102

Int J Mol Sci. 2025 Jan 3;26(1):364. doi: 10.3390/ijms26010364.

ABSTRACT

This review describes our current understanding of the role of the mitochondria in the repurposing of the anti-diabetes drugs metformin, gliclazide, GLP-1 receptor agonists, and SGLT2 inhibitors for additional clinical benefits regarding unhealthy aging, long COVID, mental neurogenerative disorders, and obesity. Metformin, the most prominent of these diabetes drugs, has been called the "Drug of Miracles and Wonders," as clinical trials have found it to be beneficial for human patients suffering from these maladies. To promote viral replication in all infected human cells, SARS-CoV-2 stimulates the infected liver cells to produce glucose and to export it into the blood stream, which can cause diabetes in long COVID patients, and metformin, which reduces the levels of glucose in the blood, was shown to cut the incidence rate of long COVID in half for all patients recovering from SARS-CoV-2. Metformin leads to the phosphorylation of the AMP-activated protein kinase AMPK, which accelerates the import of glucose into cells via the glucose transporter GLUT4 and switches the cells to the starvation mode, counteracting the virus. Diabetes drugs also stimulate the unfolded protein response and thus mitophagy, which is beneficial for healthy aging and mental health. Diabetes drugs were also found to mimic exercise and help to reduce body weight.

PMID:39796218 | DOI:10.3390/ijms26010364

Int J Mol Sci. 2025 Jan 1;26(1):315. doi: 10.3390/ijms26010315.

ABSTRACT

Eumycetoma, a chronic fungal infection caused by Madurella mycetomatis, is a neglected tropical disease characterized by tumor-like growths that can lead to permanent disability and deformities if untreated. Predominantly affecting regions in Africa, South America, and Asia, it imposes significant physical, social, and economic burdens. Current treatments, including antifungal drugs like itraconazole, often show variable efficacy, with severe cases necessitating surgical intervention or amputation. Drug discovery for eumycetoma faces challenges due to limited understanding of the disease's molecular mechanisms and the lack of 3D structures for key targets such as Madurella mycetomatis CYP51, a well-known target for azoles' antifungal agents. To address these challenges, this study employed computational approaches, including homology modeling, virtual screening, free energy calculations, and molecular dynamics simulations, to repurpose FDA-approved drugs as potential treatments for eumycetoma targeting Madurella mycetomatis CYP51. To this end, a library of 2619 FDA-approved drugs was screened, identifying three promising candidates: montelukast, vilanterol, and lidoflazine. These compounds demonstrated favorable binding affinities, strong interactions with critical residues of the homology model of Madurella mycetomatis CYP51, and stability in molecular dynamics simulations, offering potential for further investigation as effective therapeutic options for eumycetoma.

PMID:39796172 | DOI:10.3390/ijms26010315

Neurotherapeutics. 2025 Jan 9:e00522. doi: 10.1016/j.neurot.2024.e00522. Online ahead of print.

ABSTRACT

Paclitaxel (PCX) based treatments, commonly used to treat breast, ovarian and lung cancers, have the highest incidence of chemotherapy-induced neuropathic pain, affecting from 38 to 94 ​% of patients. Unfortunately, analgesic treatments are not always effective for PCX-induced neuropathic pain (PINP). This study aimed to evaluate the antinociceptive effect of clavulanic acid (CLAV), a clinically used β-lactam molecule, in both therapeutic and preventive contexts in mice with PINP. A single dose of CLAV administered after the onset of PINP significantly reduced mechanical hyperalgesia. Interestingly, preventive administration of CLAV prevented PINP development. The effect of preventive CLAV on PINP was associated with increased levels of IL-10 and IFN-β in serum, and decreased levels of IL-1β and TNF-α in both the serum and CNS. Immunostaining experiments revelated that CLAV increased the levels of glutamate transporter type 1 (GLT-1) and toll-like receptor type 4 (TLR4) in the spinal cord, while reducing levels of the astrocytic marker the glial fibrillary acidic protein (GFAP). Notably, co-incubation with CLAV and PCX in triple-negative breast cancer cells did not interfere with PCX-induced cytotoxic effects. Hence, these findings suggest that CLAV could be employed as a clinical treatment aimed at preventing PINP without compromission the cytotoxic efficacy of PCX.

PMID:39794241 | DOI:10.1016/j.neurot.2024.e00522

Mol Cell Proteomics. 2025 Jan 8:100905. doi: 10.1016/j.mcpro.2025.100905. Online ahead of print.

ABSTRACT

Protein phosphorylation plays a crucial role in regulating diverse biological processes. Perturbations in protein phosphorylation are closely associated with downstream pathway dysfunctions, while alterations in protein expression could serve as sensitive indicators of pathological status. However, there are currently few methods that can accurately identify the regulatory links between protein phosphorylation and expression, given issues like reverse causation and confounders. Here, we present Phoslink, a causal inference model to infer causal effects between protein phosphorylation and expression, integrating prior evidence and multi-omics data. We demonstrated the feasibility and advantages of our method under various simulation scenarios. Phoslink exhibited more robust estimates and lower FDR than commonly used Pearson and Spearman correlations, with better performance than canonical IV selection methods for Mendelian randomization. Applying this approach, we identified 345 causal links involving 109 phosphosites and 310 proteins in 79 lung adenocarcinoma (LUAD) samples. Based on these links, we constructed a causal regulatory network and identified 26 key regulatory phosphosites as regulators strongly associated with LUAD. Notably, 16 of these regulators were exclusively identified through phosphosite-protein causal regulatory relationships, highlighting the significance of causal inference. We explored potentially druggable phosphoproteins and provided critical clues for drug repurposing in LUAD. We also identified significant mediation between protein phosphorylation and LUAD through protein expression. In summary, our study introduces a new approach for causal inference in phosphoproteomics studies. Phoslink demonstrates its utility in potential drug target identification thereby accelerating the clinical translation of cancer proteomics and phosphoproteomic data.

PMID:39793886 | DOI:10.1016/j.mcpro.2025.100905

Eur J Med Chem. 2025 Jan 4;285:117245. doi: 10.1016/j.ejmech.2025.117245. Online ahead of print.

ABSTRACT

Breast cancer, a leading cause of cancer-related mortality in women, is characterized by genomic instability and aberrant gene expression, often influenced by noncanonical nucleic acid structures such as G-quadruplexes (G4s). These structures, commonly found in the promoter regions and 5'-untranslated RNA sequences of several oncogenes, play crucial roles in regulating transcription and translation. Stabilizing these G4 structures offers a promising therapeutic strategy for targeting key oncogenic pathways. In this study, we employed a drug repurposing approach to identify FDA-approved drugs capable of binding and stabilizing G4s in breast cancer-related genes. Using ligand-based virtual screening and biophysical methods, we identified several promising compounds, such as azelastine, belotecan, and irinotecan, as effective G4 binders, with significant antiproliferative effects in breast cancer cell lines. Notably, belotecan and irinotecan exhibited a synergistic mechanism, combining G4 stabilization with their established topoisomerase I inhibition activity to enhance cytotoxicity in cancer cells. Our findings support the therapeutic potential of G4 stabilization in breast cancer, validate drug repurposing as an efficient strategy to identify G4-targeting drugs, and highlight how combining G4 stabilization with other established drug activities may improve anticancer efficacy.

PMID:39793440 | DOI:10.1016/j.ejmech.2025.117245

Int J Environ Health Res. 2025 Jan 10:1-11. doi: 10.1080/09603123.2025.2451623. Online ahead of print.

ABSTRACT

This study utilized a validated questionnaire that aimed to assess pharmacists' awareness and attitude towards drug repurposing for antimicrobial use. Despite the reasonable awareness, pharmacists reported unfavourable attitudes. Pharmacists with a B.Pharm. or Pharm.D. degree reported less awareness than pharmacists with a master's or PhD degree. In contrast, pharmacists who dispensed fewer than 10 prescriptions or 10-29 prescriptions had significantly higher awareness than those who dispensed 30 prescriptions daily or more. Pharmacists who had 1-5 years of experience and those who dispensed less than 10 prescriptions daily had significantly lower attitude scores than their counterpats. The most reported facilitator was the reduced risk of antimicrobial resistance, while the most reported barrier was patient safety. Pharmacists' perception of drug repurposing for antimicrobial needs to improve via implementing educational sessions that highlight the impact of drug repurposing on supporting the fight against antimicrobial resistance and promoting a more sustainable and resilient healthcare system.

PMID:39792370 | DOI:10.1080/09603123.2025.2451623

J Appl Microbiol. 2025 Jan 9:lxaf012. doi: 10.1093/jambio/lxaf012. Online ahead of print.

ABSTRACT

AIMS: To investigate the effects of simvastatin as an antimicrobial, considering its influence on the mevalonate pathway and on the bacterial cell wall of Staphylococcus aureus.

METHODS AND RESULTS: S. aureus ATCC 29213 and 33591 were exposed to simvastatin in the presence of exogenous mevalonate to determine whether mevalonate could reverse the inhibition. S. aureus was also treated with simvastatin and gene expression analysis assays were performed to evaluate genes associated with the mevalonate pathway (mvaA, mvaS, mvaK1, and mvaK2), peptidoglycan synthesis (uppS, uppP, and murG), and cell wall stress (vraX, sgtB, and tcaA). Transmission electron microscopy was used to identify the presence of morphological changes. The data were compared using two-way ANOVA and Bonferroni post-test, or the Mann-Whitney test. Addition of exogenous mevalonate was able to partially or completely reverse the inhibition caused by simvastatin. A significant increase of the vraX gene and a reduction of the mvaA gene were observed, together with changes in bacterial morphology.

CONCLUSION: Simvastatin can exert its antimicrobial effect by means of changes in the cell wall associated with the mevalonate pathway.

PMID:39788721 | DOI:10.1093/jambio/lxaf012

Int J Biol Macromol. 2025 Jan 7:139590. doi: 10.1016/j.ijbiomac.2025.139590. Online ahead of print.

ABSTRACT

SARS-CoV-2 encodes a 3C-like protease (3CLpro) that is essential for viral replication. This cysteine protease cleaves viral polyproteins to release functional nonstructural proteins, making it a prime target for antiviral drug development. We investigated the inhibitory effects of halicin, a known c-Jun N-terminal kinase inhibitor, on 3CLpro. Mass spectrometry and crystallographic analysis revealed that halicin covalently binds to several cysteine residues in 3CLpro. As expected, Cys145, the catalytic residue, was found to be the most targeted residue by halicin. Secondly, Cys44 was found to be modified, suggesting a potential inhibitory role of this residue. A mutant protease (Cys44Ala) was generated to further understand the function of Cys44. In silico and enzymatic assays showed that the mutation significantly reduced the stability and activity of 3CLpro, indicating the importance of Cys44 in maintaining the active conformation of the protease. Differential scanning fluorimetry assays confirmed this evidence, showing a reduced thermal stability of the mutant compared to the wild-type protease. Our results highlight the potential of halicin as a multi-target inhibitor of 3CLpro and underline the importance of Cys44 in the function of the protease. These findings contribute to the development of effective antiviral therapies against COVID-19 by targeting critical residues in 3CLpro.

PMID:39788258 | DOI:10.1016/j.ijbiomac.2025.139590

PLoS One. 2025 Jan 9;20(1):e0314151. doi: 10.1371/journal.pone.0314151. eCollection 2025.

ABSTRACT

Aquaporin 1 (AQP1) is a key channel for water transport in peritoneal dialysis. Inhibition of AQP1 could therefore impair water transport during peritoneal dialysis. It is not known whether inhibition of AQP1 occurs unintentionally due to off-target interactions of administered medications. A high-throughput virtual screening study has been performed to investigate the possible binding of licensed medications to the water pore of human AQP1. A complete model of human AQP1 based on its canonical sequence was assembled using I-TASSER and MODELLER. The model was refined via the incorporation of pore water molecules from a high-resolution yeast aquaporin structure. Docking studies were conducted for the cytoplasmic domain of the AQP1 monomer against a library of all compounds listed in the British National Formulary (BNF), using the PLANTS software with the ChemPLP scoring function. The stability of the best docked conformations within the intrinsic water pore was assessed via short 15 nanosecond molecular dynamics (MD) simulations using the GROMACS-on-Colab utility. Of the 1512 compounds tested, 1002 docking results were obtained, and 198 of these conformations occupied a position within the intrinsic water pore. 30 compounds with promising docking scores were assessed by MD. The docked conformations for dopamine, gabapentin, pregabalin, and methyldopa were stable in these short MD studies. For furosemide and pravastatin, the MD trajectory suggested a binding mode different to the docking result. A small set of compounds which could impede water transport through human AQP1 have been identified in this computational screening study.

PMID:39787482 | DOI:10.1371/journal.pone.0314151

Alzheimers Dement. 2024 Dec;20 Suppl 2:e086490. doi: 10.1002/alz.086490.

ABSTRACT

BACKGROUND: Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Its underlying mechanisms remain elusive and specific mechanism-based drugs are lacking.

METHOD: We integrated more than 2,800 CSF and 4,600 plasma pQTL, derived from the largest proteomic studies so far (SOMAscan 7k and 4k; in up to 35,559 individuals), and the two most prevalent MRI-markers of cSVD (MRI-cSVD, white matter hyperintensities and perivascular spaces burden; in up to 48,454 individuals) in a Mendelian Randomization (MR) framework to identify causal and druggable targets for cSVD. Identified association were followed-up using a multipronged approach: across fluids, proteomics platforms (Olink 3072, N=8,590) and lifespan (N=1,748), using both MR and individual-level data.

RESULT: We found 51 proteins associated with MRI-cSVD of which 46 in CSF and 9 in plasma. Among available significant CSF- and plasma-proteins, 32% and 31% replicated in cross-fluid and cross-platform follow-up, and 47% were associated with stroke and/or dementia at least at nominal significance. We found converging evidence that protein-cSVD associations are enriched in extracellular matrix and immune response pathways. Immunity-related proteins already showed association with MRI-cSVD already in young adults in their twenties. Furthermore, we provide genetic support for drug repositioning opportunities for cSVD, including compounds crossing the blood brain barrier.

CONCLUSION: Together, these findings provide a novel proteogenomic signature of cSVD and pave the way for novel therapeutic developments.

PMID:39785542 | DOI:10.1002/alz.086490

Alzheimers Dement. 2024 Dec;20 Suppl 7:e083393. doi: 10.1002/alz.083393.

ABSTRACT

Psychosis is a common and distressing disorder in people with Alzheimer disease, associated with a poor clinical prognosis, an increased risk of institutionalization and for which there are no approved treatments. New approaches to diagnosis and symptom assessment and treatment are beginning to move the field forward, including the emergence of psychosis at the pre-clinical or even pre-cognitive impairment stages of disease in some individuals. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART) research criteria for psychosis in neurodegenerative disease, and the ISTAART criteria for mild behavioural impairment are examples of recent developments. New genomic, neuroimaging, post-mortem and neurobiology studies are beginning to refine our mechanistic understanding and providing novel opportunities for drug discovery, drug repurposing and potentially for better approaches to precision medicine. Emerging potential therapies include the 5HT2A inverse agonist pimavanserin, which is already licensed in the US for the treatment of Parkinson's disease, escitalopram, muscarinic agonists and cannabidiol. Emerging data also highlight opportunities to optimize and develop more targeted psychological therapies for people with Alzheimer's disease psychosis. The treatment of psychosis also remains a major challenge in synuclein dementias where psychosis is more frequent and more persistent, and where many patients experience severe sensitivity reactions to antipsychotic medications. There is very little work examining the mechanisms or treatment of psychosis in people with vascular dementia, which remains a major unmet need. Although the assessment and management of psychosis in people with dementia remain challenging, improved diagnosis, evolving mechanistic understanding and an increased focus on new treatment studies are providing direction and new opportunities to the field and to people with Alzheimer's disease.

PMID:39784914 | DOI:10.1002/alz.083393

J Alzheimers Dis. 2025 Jan 9:13872877241305740. doi: 10.1177/13872877241305740. Online ahead of print.

ABSTRACT

Seizures in people with Alzheimer's disease are increasingly recognized to worsen disease burden and accelerate functional decline. Harnessing established antiseizure medicine discovery strategies in rodents with Alzheimer's disease associated risk genes represents a novel way to uncover disease modifying treatments that may benefit these Alzheimer's disease patients. This commentary discusses the recent evaluation by Dejakaisaya and colleagues to assess the antiseizure and disease-modifying potential of the repurposed cephalosporin antibiotic, ceftriaxone, in the Tg2576 mouse model. The use of established epilepsy models in Alzheimer's disease research carries the potential to advance novel disease-modifying treatments.

PMID:39784685 | DOI:10.1177/13872877241305740

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095063. doi: 10.1002/alz.095063.

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is a devastating form of dementia, and its prevalence is rising as human lifespan increases. Our lab created the AD-BXD mouse model, which expresses AD mutations across a genetically diverse reference panel (BXD), to identify factors that confer resilience to cognitive decline in AD. This model mimics key characteristics of human AD including variation in age of onset and severity of cognitive decline.

METHOD: To facilitate discovery of conserved mechanisms of resilience to AD, we generated a cross-species single-nuclei transcriptomic dataset from normal and AD human (ROSMAP) and AD-BXD mouse frontal cortex tissue. We interrogated resilience-associated gene expression signatures, validated resilience candidate genes with human reference data, and used a druggability ranking and drug repositioning pipeline to nominate drugs to promote resilience to AD. To learn more about the context of resilience gene expression, we used a hierarchical mapping algorithm to predict anatomical locations of cells expressing resilience gene signatures.

RESULT: We found the strongest gene expression signature associated with cognitive resilience to AD arises from excitatory layer 4/5 (eL4/5) cortical intratelencephalic neurons. This resilience signature includes genes involved in synaptic plasticity, vesicle transport, and axonal and dendritic development. We found that 27 of the 61 genes in the resilience signature are druggable and identified several candidate drugs for further investigation (Telpoukhovskaia et al., 2022). We also identified genes expressed across a continuum of cognitive performance. Our hierarchical mapping approach showed that the eL4/5 neurons expressing resilience signature genes are distributed throughout the frontal cortex, mainly in the somatomotor area.

CONCLUSION: We identified 61 candidate resilience genes to target with new or existing drugs. We also determined that expression of resilience candidate genes occurs in eL4/5 neurons in the somatomotor region of the cortex. Ongoing projects in the lab aim to evaluate efficacy of nominated drugs and profile learning-specific proteomes of eL4/5 neurons in resilient and susceptible AD-BXD strains. When integrated with existing genetic, behavioral, and pathological data, our work will elucidate the cellular, molecular, and genetic mechanisms that contribute to cognitive resilience in face of neurodegenerative disease pathology.

PMID:39783534 | DOI:10.1002/alz.095063

Alzheimers Dement. 2024 Dec;20 Suppl 8:e095709. doi: 10.1002/alz.095709.

ABSTRACT

BACKGROUND: Cerebral amyloid angiopathy (CAA), the accumulation of amyloid proteins in the cerebral vasculature, increases the risk of stroke and vascular cognitive impairment and dementia (VCID). Not only is there no treatment for CAA, but the condition is also highly comorbid with Alzheimer's disease (AD), and its presence may serve as a contraindication to treating patients with anti-amyloid therapies due to an increased risk of hemorrhage and edema. Therefore, it is crucial to identify novel treatments for individuals with CAA. Epidemiological studies suggest that certain antihypertensive medications, including those that target the renin-angiotensin system (RAS), are associated with a decreased risk of dementia. This study assesses whether two FDA-approved RAS-targeting drugs: telmisartan [a moderately brain-penetrant angiotensin receptor blocker (ARB)], and lisinopril [a brain-penetrant angiotensin-converting enzyme (ACE) inhibitor]; can be repurposed for the treatment of CAA.

METHODS: At either ∼3 months (early intervention) or ∼8 months (later intervention) of age, male and female Tg-SwDI mice began treatment with either telmisartan (1 mg/kg/day) or lisinopril (15 mg/kg/day) dissolved in drinking water or received plain drinking water only. Age- and sex-matched C57BL/6J mice receiving plain drinking water served as wild-type controls. Following 4 months of treatment, mice underwent blood pressure measurement followed by behavioral testing prior to euthanasia.

RESULTS: Voluntary oral consumption delivered doses similar to the target dose for both drugs. At the doses used, telmisartan and lisinopril treatment did not significantly reduce blood pressure in Tg-SwDI mice. Our findings thus far suggest that these drug treatments, particularly lisinopril, may mitigate cognitive-behavioral deficits observed in Tg-SwDI mice.

CONCLUSIONS: Ongoing experiments are being completed to increase sample sizes and investigate the potential benefits of telmisartan and lisinopril to mitigate neuropathological and cognitive impairment in Tg-SwDI mice. If findings support our hypothesis, this will demonstrate that these drugs could be repurposed to prevent and/or treat CAA, reducing the worldwide burden of stroke and dementia.

PMID:39783163 | DOI:10.1002/alz.095709

Alzheimers Dement. 2024 Dec;20 Suppl 6:e089679. doi: 10.1002/alz.089679.

ABSTRACT

BACKGROUND: Developing drugs for treating Alzheimer's disease (AD) has been extremely challenging and costly due to limited knowledge on underlying biological mechanisms and therapeutic targets. Repurposing drugs or their combination has shown potential in accelerating drug development due to the reduced drug toxicity while targeting multiple pathologies.

METHOD: To address the challenge in AD drug development, we developed a multi-task machine learning pipeline to integrate a comprehensive knowledge graph on biological/pharmacological interactions and multi-level evidence on drug efficacy, to identify repurposable drugs and their combination candidates RESULT: Using the drug embedding from the heterogeneous graph representation model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, mechanistic efficacy in preclinical models, population-based treatment effect, and Phase 2/3 clinical trials. We experimentally validated the top-ranked candidates in neuronal cells, identifying drug combinations with efficacy in reducing oxidative stress and safety in maintaining neuronal viability and morphology. Our neuronal response experiments confirmed several biologically efficacious drug combinations.

CONCLUSION: This methodology showed that harmonizing heterogeneous and complementary data/knowledge, including human interactome, transcriptome patterns, experimental efficacy, and real-world patient data shed light on the drug development of complex diseases.

PMID:39782643 | DOI:10.1002/alz.089679

Alzheimers Dement. 2024 Dec;20 Suppl 6:e086778. doi: 10.1002/alz.086778.

ABSTRACT

BACKGROUND: Despite increasing knowledge of the etiology of neurodegenerative diseases, translation of these benefits into therapeutic advances for Alzheimer's Disease and related diseases (ADRD) has been slow. Drug repurposing is a promising strategy for identifying new uses for approved drugs beyond their initial indications. We developed a high-throughput drug screening platform aimed at identifying drugs capable of reducing proteotoxicity in vivo (Aß toxicity in Caenorhabditis elegans) AND inhibiting microglial inflammation (TNF-alpha IL-6), both implicated in driving AD(figure attached with sample of results in C. elegans). These screens led us to prioritize 50 potentially protective FDA-approved drugs. We propose to test our screening results in humans using administrative claims data collected from the Centers for Medicare and Medicaid Services METHOD: This is an observational retrospective pharmaco-epidemiological longitudinal cohort study. The cohort is a random sample of 1,000,000 beneficiaries, aged 65-75 years, followed for 10 consecutive years, requested from CMS. Files include MedPar, Outpatient, Carrier, Hospice to maximize inclusion of AD beneficiaries according to Bynum algorithm, and Part D event for drug prescription details. We will use Cox regression, to compute Hazard Ratios and associated 95% confidence intervals, of the association between drug exposure status and the risk of ADRD. We will examine potential confounding by indication, drug target, and competing risks.

RESULT: 1/We propose to assess if drugs which reduce Ab toxicity in a C. elegans model of AD AND reduce microglial inflammation reduce the risk of developing ADRD in humans, using Medicare claims. 2/We propose to assess if drugs which reduce inflammation, reduce the risk of developing ADRD in humans, using the Medicare claims.

CONCLUSION: The end goal of the study is to identify drugs to be repurposed to treat ADRD and to accumulate strong epidemiological evidence in addition to the existing evidence from the model organism C. elegans and cell culture studies.

PMID:39782522 | DOI:10.1002/alz.086778

Alzheimers Dement. 2024 Dec;20 Suppl 6:e087380. doi: 10.1002/alz.087380.

ABSTRACT

BACKGROUND: Global epidemiological studies involving over nine million participants have shown a 35% lower incidence of Alzheimer's Disease (AD) in older cancer survivors compared to those without a history of cancer. This inverse relationship, consistent across recent studies with methodological controls, suggests that cancer itself, rather than cancer treatments, may offer protective factors against AD. This insight opens avenues for novel therapeutic strategies targeting early AD by harnessing cancer-associated protective factors.

METHODS: To investigate the potential protective effect of cancer against Alzheimer's Disease (AD), we developed "cancer-in-AD" mouse models. These models involved injecting a small number of breast cancer cells into young AD-model mice (5xFAD) and monitoring amyloid plaque progression. Additionally, we introduced extracellular vesicles (EVs) from breast tumor-bearing mice into similar AD models. Using spatial transcriptomics, we analyzed brain tissue gene expression and cell-cell interactions, focusing on the astrocyte-microglia-oligodendrocyte network near amyloid plaques. This approach helped identify potential drugs for repurposing in AD treatment.

RESULTS: The study found a significant reduction in amyloid burden within the brains of the cancer-in-AD mouse models compared to age-matched cancer-free AD mice. The administration of EVs from cancer animal's plasma to the AD mice prompted the release of various inflammatory cytokines and chemokines. A key discovery was an activated astrocyte-microglia-oligodendrocyte signaling network that regulates amyloid-beta homeostasis in these mouse brains. Out of 49 FDA-approved drugs identified to induce this cancer-induced signaling, 11 showed promise in improving AD symptoms and reducing amyloid and tau accumulations, in both preclinical and clinical studies.

CONCLUSIONS: The study reveals a notable decrease in amyloid levels in AD mice with cancer or exposed to tumor-derived EVs, linked to immune system reprogramming and glial network activation. This supports the study's drug repositioning approach and sets the stage for further research into the anti-AD properties of these drugs, focusing on identifying crucial signaling elements for enhanced drug repositioning and combination treatment strategies.

PMID:39782516 | DOI:10.1002/alz.087380