Challenges and Opportunities for Consideration of Efavirenz Drug Repurposing for Alzheimer’s Disease Therapeutics DOI Creative Commons

Ben Boyarko,

Sonia Podvin,

Barry Greenberg

и другие.

ACS Pharmacology & Translational Science, Год журнала: 2024, Номер 7(10), С. 2924 - 2935

Опубликована: Сен. 6, 2024

Therapeutic research and development for Alzheimer's disease (AD) has been an area of intense to alleviate memory loss neurodegeneration. There is growing interest in drug repositioning repurposing strategies FDA-approved medications as potential candidates that may further advance AD therapeutics. The FDA efavirenz investigated a candidate medication. proposed mechanism action (at low doses) the activation neuron-specific enzyme CYP46A1 converts excess brain cholesterol into 24-hydroxycholesterol (24-HC) exported periphery. Efavirenz at dose was found improve deficit 5XFAD model accompanied by elevated 24-HC reduction Aβ; furthermore, reduced pTau levels human iPSC-derived neurons. used mouse increase contrasts with use more than 100-fold higher doses clinical treatment immunodeficiency virus (HIV) through inhibition reverse transcriptase. Low avoid neurotoxic adverse effects occur high HIV treatment. This review evaluates properties respect its preclinical data on regulating deficit, pharmacokinetics, pharmacodynamics, metabolites, genetic variabilities metabolism well effects. These analyses discuss challenges questions should be addressed future studies consider opportunity development.

Язык: Английский

Neuronal polyunsaturated fatty acids are protective in ALS/FTD DOI Creative Commons
A Giblin, Alexander J. Cammack,

Niek Blomberg

и другие.

Nature Neuroscience, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Abstract Here we report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in Drosophila model C9orf72 repeat expansion, the most common genetic cause amyotrophic lateral sclerosis frontotemporal dementia (ALS/FTD), human postmortem ALS spinal cord. We performed lipidomics on C9 ALS/FTD , induced pluripotent stem (iPS) cell neurons FTD brain tissue. This revealed specific reduction phospholipid species containing polyunsaturated acids (PUFAs). Feeding flies PUFAs yielded modest increase survival. However, increasing PUFA levels specifically flies, by overexpressing desaturase enzymes, led to substantial extension lifespan. Neuronal overexpression desaturases also suppressed stressor-induced neuronal death iPS patients with both TDP-43 ALS/FTD. These data implicate saturation pathogenesis suggest that interventions may be beneficial.

Язык: Английский

Процитировано

2
Contributions of Genetic Variation in Astrocytes to Cell and Molecular Mechanisms of Risk and Resilience to Late‐Onset Alzheimer's Disease DOI Creative Commons
Hyo Lee, Richard V. Pearse,

Alexandra M. Lish

и другие.

Glia, Год журнала: 2025, Номер unknown

Опубликована: Фев. 3, 2025

ABSTRACT Reactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants genes highly expressed in astrocytes. However, the contribution of within to cellular processes relevant pathogenesis remains ill‐defined. Here, we present a resource for studying using large collection induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals range neuropathological cognitive outcomes. IPSC 44 were differentiated into followed by unbiased molecular profiling RNA sequencing tandem mass tag‐mass spectrometry. We demonstrate utility this examining gene‐ pathway‐level associations clinical traits, as well analyzing resilience factors through parallel analyses iPSC‐astrocytes brain tissue same individuals. Our reveal that pathways altered iPSC‐derived concordantly dysregulated tissue. This includes increased levels prefoldin proteins, extracellular matrix factors, COPI‐mediated trafficking components reduced proteins involved respiration fatty acid oxidation. Additionally, resilient high neuropathology show elevated basal interferon response secretion gamma. Correspondingly, higher polygenic scores lower study establishes an experimental system integrates information matched iPSC data cohort identify contributions affecting resilience.

Язык: Английский

Процитировано

1
Contribution of Brain Intrinsic Branched‐Chain Amino Acid Metabolism in a Novel Mouse Model of Maple Syrup Urine Disease DOI Open Access

Amanda Kuhs,

Laura Ohl,

Tegan Thurston

и другие.

Journal of Inherited Metabolic Disease, Год журнала: 2025, Номер 48(2)

Опубликована: Фев. 4, 2025

Язык: Английский

Процитировано

1
Advancements in Mass Spectrometry-Based Targeted Metabolomics and Lipidomics: Implications for Clinical Research DOI Creative Commons
Nguyen Ky Anh,

Nguyen Quang Thu,

Nguyen Tran Nam Tien

и другие.

Molecules, Год журнала: 2024, Номер 29(24), С. 5934 - 5934

Опубликована: Дек. 16, 2024

Targeted metabolomics and lipidomics are increasingly utilized in clinical research, providing quantitative comprehensive assessments of metabolic profiles that underlie physiological pathological mechanisms. These approaches enable the identification critical metabolites alterations essential for accurate diagnosis precision treatment. Mass spectrometry, combination with various separation techniques, offers a highly sensitive specific platform implementing targeted settings. Nevertheless, challenges persist areas such as sample collection, quantification, quality control, data interpretation. This review summarizes recent advances lipidomics, emphasizing their applications research. Advancements, including microsampling, dynamic multiple reaction monitoring, integration ion mobility mass highlighted. Additionally, discusses importance standardization harmonization successful implementation.

Язык: Английский

Процитировано

4
iSODA: A Comprehensive Tool for Integrative Omics Data Analysis in Single- and Multi-Omics Experiments DOI Creative Commons
Damien Olivier‐Jimenez, Rico J. E. Derks, Oscar Harari

и другие.

Analytical Chemistry, Год журнала: 2025, Номер 97(5), С. 2689 - 2697

Опубликована: Янв. 31, 2025

Thanks to the plummeting costs of continuously evolving omics analytical platforms, research centers collect multiomics data more routinely. They are, however, confronted with lack a versatile software solution harmoniously analyze single-omics and interpret data. We have developed iSODA, web-based application for analysis single- The tool emphasizes intuitive interactive visualizations designed user-driven exploration. Researchers can access variety functions ranging from simple visualization like volcano plots PCA advanced functional analyses enrichment lipid saturation analysis. For integrated multiomics, iSODA incorporates multi-omics factor similarity network fusion. ability adapt on-the-fly allows tasks, such as removal outlier samples or failed features, imputation, normalization. All results are presented through plots, modular design supports extensions, tooltips tutorials provide comprehensive guidance users. is accessible under http://isoda.online/.

Язык: Английский

Процитировано

0
Regulation of glial ApoE secretion by the mevalonate pathway is independent of ApoE isoform DOI Creative Commons
Joshua L. Milstein, Joshua A. Kulas,

Anupama Kamal

и другие.

Journal of Alzheimer s Disease, Год журнала: 2025, Номер unknown

Опубликована: Фев. 24, 2025

Background Lipids synthesized in astrocytes are distributed to other brain cells high-density lipoprotein-like ApoE particles. ApoE, which is a powerful genetic risk factor for developing Alzheimer's disease, secreted differently depending on genotype. Secretion of from mouse regulated by the mevalonate pathway. Objective We aimed understand if regulation secretion pathway was same between and humanized mice, this impacted isoform. Methods Astrocyte-enriched glial cultures wild-type targeted-replacement mice were treated with pharmacological inhibitors various steps along conditioned media measured. Results show that statins prenylation inhibitors, but not specific cholesterol reduce extracellular lipoparticle levels astrocyte-enriched cultures, occurs harboring either or any three human genotypes similar extent. find geranylgeranylation modulates release astrocytes, it does so independent Conclusions Our results suggest broadly regulates regardless genotype, mediated specifically geranylgeranylation. Therefore, our data implicates as general mechanism modulating likely responsible reported baseline differences seen vivo vitro across genotypes.

Язык: Английский

Процитировано

0
Contributions of genetic variation in astrocytes to cell and molecular mechanisms of risk and resilience to late onset Alzheimer’s disease DOI Open Access
Hyo Lee, Richard V. Pearse,

Alexandra M. Lish

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 31, 2024

Reactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants genes highly expressed in astrocytes. However, the contribution of within to cellular processes relevant pathogenesis remains ill-defined. Here we present a resource for studying using large collection induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals range neuropathological cognitive outcomes. IPSC forty-four were differentiated into followed by unbiased molecular profiling RNA sequencing tandem mass tag-mass spectrometry. We demonstrate utility this examining gene- pathway-level associations clinical traits, as well analyzing resilience factors through parallel analyses iPSC-astrocytes brain tissue same individuals. Our reveal that pathways altered iPSC-derived concordantly dysregulated tissue. This includes increased prefoldin proteins, extracellular matrix factors, COPI-mediated trafficking components reduced proteins involved respiration fatty acid oxidation. Additionally, resilient high neuropathology show elevated basal levels interferon response secretion gamma. Correspondingly, higher polygenic scores lower proteins. study establishes an experimental system integrates information heterogeneous set iPSCs identify contributions affecting resilience.

Язык: Английский

Процитировано

0
iSODA: A Comprehensive Tool for Integrative Omics Data Analysis in Single- and Multi-Omics Experiments DOI Creative Commons
Damien Olivier‐Jimenez, Rico J. E. Derks, Oscar Harari

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 6, 2024

Abstract Omics technologies including genomics, proteomics, metabolomics, and lipidomics allow profound insights into health disease. Thanks to plummeting costs of continuously evolving omics analytical platforms, research centers collect multi-omics data more routinely. They are, however, confronted with the lack a versatile software solution harmoniously analyze single-omics merge interpret data. We have developed iSODA, an interactive web-based application for analysis single-as well as The tool emphasizes intuitive, visualizations designed user-driven exploration. Researchers can filter normalize their datasets access variety functions ranging from simple visualization like volcano plots PCA, advanced functional analyses enrichment proteomics saturation lipidomics. For integrated multi-omics, iSODA incorporates Multi-Omics Factor Analysis – MOFA, Similarity Network Fusion SNF. All results are presented in possibility downloading associated ability adapt imported on-the-fly allows tasks such removal outlier samples or failed features, various imputation strategies, normalization. modular design extensions new plots. is accessible under http://isoda.online/ . Figure Graphical summary showcasing some examples, import, modules.

Язык: Английский

Процитировано

0
Challenges and Opportunities for Consideration of Efavirenz Drug Repurposing for Alzheimer’s Disease Therapeutics DOI Creative Commons

Ben Boyarko,

Sonia Podvin,

Barry Greenberg

и другие.

ACS Pharmacology & Translational Science, Год журнала: 2024, Номер 7(10), С. 2924 - 2935

Опубликована: Сен. 6, 2024

Therapeutic research and development for Alzheimer's disease (AD) has been an area of intense to alleviate memory loss neurodegeneration. There is growing interest in drug repositioning repurposing strategies FDA-approved medications as potential candidates that may further advance AD therapeutics. The FDA efavirenz investigated a candidate medication. proposed mechanism action (at low doses) the activation neuron-specific enzyme CYP46A1 converts excess brain cholesterol into 24-hydroxycholesterol (24-HC) exported periphery. Efavirenz at dose was found improve deficit 5XFAD model accompanied by elevated 24-HC reduction Aβ; furthermore, reduced pTau levels human iPSC-derived neurons. used mouse increase contrasts with use more than 100-fold higher doses clinical treatment immunodeficiency virus (HIV) through inhibition reverse transcriptase. Low avoid neurotoxic adverse effects occur high HIV treatment. This review evaluates properties respect its preclinical data on regulating deficit, pharmacokinetics, pharmacodynamics, metabolites, genetic variabilities metabolism well effects. These analyses discuss challenges questions should be addressed future studies consider opportunity development.

Язык: Английский

Процитировано

0