Identifying brain-penetrant small molecule modulators of human microglia using a cellular model of synaptic pruning DOI Creative Commons
Liam McCrea, Rebecca Batorsky,

Joshua Bowen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 23, 2024

Abstract Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in scalable assay, we screened 489 CNS-penetrant compounds for microglial phagocytosis human synaptosomes validated assay microglia-mediated synaptic pruning. Compounds from the library that reduced by ≥2 standard deviations without cytotoxicity were secondary screens, with 28 them further confirmed to reduce 50% or more. Image-based morphological measurements calculated measure degree ramified vs. amoeboid morphotype as an indicator activation state. Additionally, transcriptomic profiling indicated divergent effects on cell signaling, metabolism, activation, actin dynamics compounds. In particular, multiple small molecules prior FDA approval demonstration safety vivo demonstrated modulatory microglia. These potential disease-modifying agents represent high-priority candidates repositioning studies neurodevelopmental, neuroinflammatory, disorders.

Language: Английский

Investigating the impact of omega-3 fatty acids on oxidative stress and pro-inflammatory cytokine release in iPSC-derived forebrain cortical neurons from ADHD patients DOI Creative Commons

Natalie Monet Walter,

Cristine Marie Yde Ohki, Lukasz Smigielski

et al.

Journal of Psychiatric Research, Journal Year: 2025, Volume and Issue: 182, P. 257 - 269

Published: Jan. 10, 2025

Language: Английский

Citations

1
Beyond the Neuron: The Integrated Role of Glia in Psychiatric Disorders DOI Creative Commons
André Demambre Bacchi

Neuroglia, Journal Year: 2025, Volume and Issue: 6(2), P. 15 - 15

Published: March 25, 2025

In recent decades, substantial evidence has highlighted the integral roles of neuroglia, particularly astrocytes, microglia, oligodendrocytes, and ependymal cells, in regulation synaptic transmission, metabolic support, immune mechanisms within central nervous system. addition to their structural role, these cells actively modulate neurotransmitter homeostasis influence neuronal plasticity, thereby affecting cognition, mood, behavior. This review discusses how neuroglial alterations contribute pathophysiology five common psychiatric disorders: major depression, bipolar disorder, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), schizophrenia. We synthesized preclinical clinical findings illustrating that glial dysfunction, including impaired myelination aberrant neuroinflammatory responses, often parallels disease onset severity. Moreover, we outline disruptions astrocytic glutamate uptake, microglia-mediated pruning, blood–brain barrier integrity may underlie neurobiological heterogeneity observed disorders. The therapeutic implications range from anti-inflammatory agents investigational compounds aim stabilize function or promote remyelination. However, challenges due interindividual variability, insufficient biomarkers, multifactorial nature illnesses remain. Advances neuroimaging, liquid biopsy, more precise molecular techniques facilitate targeted interventions by stratifying patient subgroups with distinct phenotypes. Continued research is essential translate insights into clinically efficacious safe treatments.

Language: Английский

Citations

0
Identifying brain-penetrant small-molecule modulators of human microglia using a cellular model of synaptic pruning DOI Creative Commons
Liam McCrea, Rebecca Batorsky,

Joshua Bowen

et al.

Neuropsychopharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: May 9, 2025

Language: Английский

Citations

0
Identifying brain-penetrant small molecule modulators of human microglia using a cellular model of synaptic pruning DOI Creative Commons
Liam McCrea, Rebecca Batorsky,

Joshua Bowen

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 23, 2024

Abstract Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in scalable assay, we screened 489 CNS-penetrant compounds for microglial phagocytosis human synaptosomes validated assay microglia-mediated synaptic pruning. Compounds from the library that reduced by ≥2 standard deviations without cytotoxicity were secondary screens, with 28 them further confirmed to reduce 50% or more. Image-based morphological measurements calculated measure degree ramified vs. amoeboid morphotype as an indicator activation state. Additionally, transcriptomic profiling indicated divergent effects on cell signaling, metabolism, activation, actin dynamics compounds. In particular, multiple small molecules prior FDA approval demonstration safety vivo demonstrated modulatory microglia. These potential disease-modifying agents represent high-priority candidates repositioning studies neurodevelopmental, neuroinflammatory, disorders.

Language: Английский

Citations

0