Na, N. | bioRxiv Science

bioRxiv2026

Atypical tetracyclines promote longevity and ferroptotic neuroprotection via translation attenuation

Preclinical and clinical studies have reported neuroprotective and geroprotective effects of tetracyclines that are independent of their antibiotic activity, but the underlying mechanisms remain unclear. Here, we systematically profile widely used tetracyclines, including impurities and degradation products, and identify translation attenuation as the shared driver of their neuroprotective and longevity-promoting effects, independent of classical tetracycline mechanisms. Instead, we uncover two mechanistically distinct classes of tetracyclines. Mitochondrial-targeting tetracyclines (MitoTets), exemplified by doxycycline, inhibit the mitochondrial ribosome and attenuate cytosolic translation through activation of the Integrated Stress Response (ISR). In contrast, atypical tetracyclines such as 4-epiminocycline and 12-aminominocycline act as cytosolic-targeting tetracyclines (CytoTets), directly inhibiting the cytosolic ribosome, bypassing the ISR, and protecting neurons from ferroptotic cell death. CytoTets are non-antibiotic, brain-penetrant, and neuroprotective in mouse and human neurons, establishing the tetracyclines as a tunable chemical scaffold for selectively targeting translation in aging and neurodegeneration. HighlightsO_LIThe tetracyclines broadly attenuate translation in multiple eukaryotic models C_LIO_LITranslation attenuation results from both ISR-dependent and ISR-independent mechanisms C_LIO_LIDiscovery of atypical, cytosolic targeting tetracyclines (CytoTETs) that protect from ferroptosis ISR-independently C_LIO_LICytoTETs inhibit translation and are neuroprotective in human-derived neurons and mouse hippocampus C_LI

pharmacology and toxicology↗

bioRxiv2025

Microglia-to-neuron signaling increases lipid droplet metabolism, enhancing neuronal network activity

Microglia regulate neuronal circuit plasticity. Disrupting their homeostatic function has detrimental effects on neuronal circuit health. Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, including Alzheimers disease (AD), with several microglial activation genes linked to increased risk for these conditions. Inflammatory microglia alter neuronal excitability, inducing metabolic strain. Interestingly, expression of APOE4, the strongest genetic risk factor for AD, affects both microglial activation and neuronal excitability, highlighting the interplay between lipid metabolism, inflammation, and neuronal function. It remains unclear how microglial inflammatory state is conveyed to neurons to affect circuit function and whether APOE4 expression alters this intercellular communication. Here, we use a reductionist model of human iPSC-derived microglial and neuronal monocultures to dissect how the APOE genotype in each cell-type independently contributes to microglial regulation of neuronal activity during inflammation. Conditioned media (CM) from LPS-stimulated microglia increased neuronal network activity, assessed by calcium imaging, with APOE4 microglial CM driving higher neuronal firing rates than APOE3 CM. Both APOE3 and APOE4 neurons increase network activity in response to CM treatments, while APOE4 neurons uniquely increase presynaptic puncta with APOE4 microglial CM. CM-derived exosomes from LPS-stimulated microglia can mediate increases to network activity. Lastly, increased network activity is accompanied by increased lipid droplet (LD) metabolism and blocking LD metabolism abolishes network activity. These findings illuminate how microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function, demonstrate a role for neuronal LDs in network activity, and support a potential mechanism through which APOE4 increases neuronal excitability.

neuroscience↗