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In neurodegenerative diseases, debris of dead neurons are thought to trigger glia-mediated neuroinflammation, thus increasing neuronal death. Here we show that the expression of neurotoxic proteins associated with these diseases in microglia alone is sufficient to directly trigger death of naive neurons and to propagate neuronal death through activation of naive astrocytes to the A1 state. Injury propagation is mediated, in great part, by the release of fragmented and dysfunctional microglial mitochondria into the neuronal milieu. The amount of damaged mitochondria released from microglia relative to functional mitochondria and the consequent neuronal injury are determined by Fis1-mediated mitochondrial fragmentation within the glial cells. The propagation of the inflammatory response and neuronal cell death by extracellular dysfunctional mitochondria suggests a potential new intervention for neurodegeneration—one that inhibits mitochondrial fragmentation in microglia, thus inhibiting the release of dysfunctional mitochondria into the extracellular milieu of the brain, without affecting the release of healthy neuroprotective mitochondria.

Animal studies show aging varies between individuals as well as between organs within an individual 1 – 4 , but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20–50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer’s disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5 ), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects. Blood plasma protein data was combined with machine learning models for a simple method to determine differences in organ-specific aging; the study provides a basis for the prediction of diseases and aging effects using plasma proteomics.

Background Out of the myriad of complications associated with septic shock, septic-associated encephalopathy (SAE) carries a significant risk of morbidity and mortality. Blood-brain-barrier (BBB) impairment, which subsequently leads to increased vascular permeability, has been associated with neuronal injury in sepsis. Thus, preventing BBB damage is an attractive therapeutic target. Mitochondrial dysfunction is an important contributor of sepsis-induced multi-organ system failure. More recently, mitochondrial dysfunction in endothelial cells has been implicated in mediating BBB failure in stroke, multiple sclerosis and in other neuroinflammatory disorders. Here, we focused on Drp1-mediated mitochondrial dysfunction in endothelial cells as a potential target to prevent BBB failure in sepsis. Methods We used lipopolysaccharide (LPS) to induce inflammation and BBB disruption in a cell culture as well as in murine model of sepsis. BBB disruption was assessed by measuring levels of key tight-junction proteins. Brain cytokines levels, oxidative stress markers, and activity of mitochondrial complexes were measured using biochemical assays. Astrocyte and microglial activation were measured using immunoblotting and qPCR. Transwell cultures of brain microvascular endothelial cells co-cultured with astrocytes were used to assess the effect of LPS on expression of tight-junction proteins, mitochondrial function, and permeability to fluorescein isothiocyanate (FITC) dextran. Finally, primary neuronal cultures exposed to LPS were assessed for mitochondrial dysfunction. Results LPS induced a strong brain inflammatory response and oxidative stress in mice which was associated with increased Drp1 activation and mitochondrial localization. Particularly, Drp1-(Fission 1) Fis1-mediated oxidative stress also led to an increase in expression of vascular permeability regulators in the septic mice. Similarly, mitochondrial defects mediated via Drp1-Fis1 interaction in primary microvascular endothelial cells were associated with increased BBB permeability and loss of tight-junctions after acute LPS injury. P110, an inhibitor of Drp1-Fis1 interaction, abrogated these defects, thus indicating a critical role for this interaction in mediating sepsis-induced brain dysfunction. Finally, LPS mediated a direct toxic effect on primary cortical neurons, which was abolished by P110 treatment. Conclusions LPS-induced impairment of BBB appears to be dependent on Drp1-Fis1-mediated mitochondrial dysfunction. Inhibition of mitochondrial dysfunction with P110 may have potential therapeutic significance in septic encephalopathy.

To date, brain imaging has largely relied on X-ray computed tomography and magnetic resonance angiography, with their limited spatial resolution and long scanning times. Fluorescence-based brain imaging in the visible and traditional near-infrared regions (400–900 nm) is an alternative, but at present it requires craniotomy, cranial windows and skull-thinning techniques, and the penetration depth is limited to 1–2 mm due to light scattering. Here, we report through-scalp and through-skull fluorescence imaging of mouse cerebral vasculature without craniotomy, utilizing the intrinsic photoluminescence of single-walled carbon nanotubes in the 1.3–1.4 μm near-infrared window (NIR-IIa window). Reduced photon scattering in this spectral region allows fluorescence imaging to a depth of >2 mm in mouse brain with sub-10-μm resolution. An imaging rate of ∼5.3 frames per second allows for dynamic recording of blood perfusion in the cerebral vessels with sufficient temporal resolution, providing real-time assessment of a blood flow anomaly in a mouse middle cerebral artery occlusion stroke model. Near-infrared photoluminescence from carbon nanotubes makes it possible to optically image the vasculature in the brain directly through the skull.

Tumor necrosis factor (TNF) drives chronic inflammation and cell death in the intestine, and blocking TNF is a therapeutic approach in inflammatory bowel disease (IBD). Despite this knowledge, the pathways that protect the intestine from TNF are incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3s) protect the intestinal epithelium from TNF-induced cell death. This occurs independent of interleukin-22 (IL-22), and we identify that ILC3s are a dominant source of heparin-binding epidermal growth factor–like growth factor (HB-EGF). ILC3s produce HB-EGF in response to prostaglandin E2 (PGE2) and engagement of the EP2 receptor. Mice lacking ILC3-derived HB-EGF exhibit increased susceptibility to TNF-mediated epithelial cell death and experimental intestinal inflammation. Finally, human ILC3s produce HB-EGF and are reduced from the inflamed intestine. These results define an essential role for ILC3-derived HB-EGF in protecting the intestine from TNF and indicate that disruption of this pathway contributes to IBD.TNF is an important driver of many inflammatory diseases. Zhou et al. demonstrate ILC3 production of the growth factor HB-EGF protects against TNF-mediated injury of the gut epithelium in inflammatory bowel disease.

Aging is associated with loss of circadian immune responses and circadian gene transcription in peripheral macrophages. Microglia, the resident macrophages of the brain, also show diurnal rhythmicity in regulating local immune responses and synaptic remodeling. To investigate the interaction between aging and microglial circadian rhythmicity, we examined mice deficient in the core clock transcription factor, BMAL1. Aging Cd11b cre ;Bmal lox/lox mice demonstrated accelerated cognitive decline in association with suppressed hippocampal long-term potentiation and increases in immature dendritic spines. C1q deposition at synapses and synaptic engulfment were significantly decreased in aging Bmal1 -deficient microglia, suggesting that BMAL1 plays a role in regulating synaptic pruning in aging. In addition to accelerated age-associated hippocampal deficits, Cd11b cre ;Bmal lox/lox mice also showed deficits in the sleep–wake cycle with increased wakefulness across light and dark phases. These results highlight an essential role of microglial BMAL1 in maintenance of synapse homeostasis in the aging brain.

Background Aging exacerbates post-stroke inflammation, contributing to worse neurological outcomes. However, the mechanisms underlying this age-dependent immune dysregulation remain unclear. Because immune cell metabolism critically shapes inflammatory responses, we investigated whether the metabolic state of circulating monocytes, key immune cells that traffic to the ischemic brain, is altered by age after stroke. We further examined whether enhancing cellular NAD + availability with nicotinamide riboside (NR) could mitigate age-associated neuroinflammatory responses and improve stroke outcome. Methods Ischemic stroke was induced in young and aged mice using the distal middle cerebral artery occlusion model. We assessed monocyte metabolic profiles via untargeted metabolomics, mitochondrial function assays, multi-analyte cytokine/chemokine profiling, and flow cytometry. Given the contribution of monocyte-derived intestinal macrophages to gut barrier disruption after stroke, we evaluated gut barrier integrity, immune cell composition, and systemic inflammation. Stroke outcomes were also determined by infarct size, motor function, and brain inflammatory status. Results Our findings show that the availability of the essential energy co-factor, NAD + , is a key age-dependent factor that regulates monocyte and intestinal macrophage immune responses after stroke. Aged monocytes showed decreased NAD + levels and increased inflammatory responses compared to young monocytes. Pretreatment with NR elevated cellular NAD + levels in aged monocytes, normalized intestinal macrophage numbers and activation states, preserved gut barrier integrity, reduced systemic and brain inflammation, and improved stroke outcomes in aged mice. Conclusion These findings highlight the importance of NAD + in mitigating the post-stroke response in aging and the potential of NAD + supplementation as a preventive strategy for patients at risk for cerebrovascular disease.

The clinical course and treatment of neurodegenerative disease are complicated by immune-system interference and chronic inflammatory processes, which remain incompletely understood. Mapping immune signatures in larger human cohorts through single-cell gene expression profiling supports our understanding of observed peripheral changes in neurodegeneration. Here, we employ single-cell gene expression profiling of over 909k peripheral blood mononuclear cells (PBMCs) from 121 healthy individuals, 48 patients with mild cognitive impairment (MCI), 46 with Parkinson’s disease (PD), 27 with Alzheimer’s disease (AD), and 15 with both PD and MCI. The dataset is interactively accessible through a freely available website ( https://www.ccb.uni-saarland.de/adrcsc ). In this work, we identify disease-associated changes in blood cell type composition and the gene expression in a sex-specific manner, offering insights into peripheral and solid tissue signatures in AD and PD. Neurodegenerative diseases are linked to changes in the immune system and inflammation. Here, the authors studied immune cells from healthy individuals and neurodegenerative diseases and identified sex-specific disease-associated changes.

Aldehyde dehydrogenase 2 deficiency (ALDH2*2) causes facial flushing in response to alcohol consumption in approximately 560 million East Asians. Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer’s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE ε4 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11 weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-β, and neuroinflammation were higher in the brains of the ALDH2*2/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in Aβ, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.

Mitochondria are the main site for generating reactive oxygen species, which are key players in diverse biological processes. However, the molecular pathways of redox signal transduction from the matrix to the cytosol are poorly defined. Here we report an inside-out redox signal of mitochondria. Cysteine oxidation of MIC60, an inner mitochondrial membrane protein, triggers the formation of disulfide bonds and the physical association of MIC60 with Miro, an outer mitochondrial membrane protein. The oxidative structural change of this membrane-crossing complex ultimately elicits cellular responses that delay mitophagy, impair cellular respiration and cause oxidative stress. Blocking the MIC60–Miro interaction or reducing either protein, genetically or pharmacologically, extends lifespan and health-span of healthy fruit flies, and benefits multiple models of Parkinson’s disease and Friedreich’s ataxia. Our discovery provides a molecular basis for common treatment strategies against oxidative stress. Redox signal transduction from the mitochondrial matrix to the cytosol is shown to be mediated through interaction between MIC60 and Miro, the disruption of which ameliorates oxidative stress in Drosophila .