Studies

The incidence of Alzheimer’s disease (AD), the leading cause of dementia, increases rapidly with age, but why age constitutes the main risk factor is still poorly understood. Brain ageing affects oligodendrocytes and the structural integrity of myelin sheaths1, the latter of which is associated with secondary neuroinflammation2,3. As oligodendrocytes support axonal energy metabolism and neuronal health4,5,6,7, we hypothesized that loss of myelin integrity could be an upstream risk factor for ...

Amyloid-β (Aβ) is thought to be neuronally derived in Alzheimer’s disease (AD). However, transcripts of amyloid precursor protein (APP) and amyloidogenic enzymes are equally abundant in oligodendrocytes (OLs). By cell-type-specific deletion of Bace1 in a humanized knock-in AD model, APPNLGF, we demonstrate that OLs and neurons contribute to Aβ plaque burden. For rapid plaque seeding, excitatory projection neurons must provide a threshold level of Aβ. Ultimately, our findings are relevant for AD ...

Concussions are a current health concern and account for the vast majority of head trauma. While symptoms after a single impact are usually transient, repetitive concussions, as often occur in sports, are responsible for persistent acute and chronic deficits. Here, we used a model of bilateral midline-centered concussions in mice to show that repetitive concussions selectively induce impairments in learning ability compared to single-impact injuries. Since microglial cells and their activation ...

T-cell receptor (TCR)-induced Ca2+ signals are essential for T-cell activation and function. In this context, mitochondria play an important role and take up Ca2+ to support elevated bioenergetic demands. However, the functional relevance of the mitochondrial-Ca2+-uniporter (MCU) complex in T-cells was not fully understood. Here, we demonstrate that TCR activation causes rapid mitochondrial Ca2+ (mCa2+) uptake in primary naive and effector human CD4+ T-cells. Compared to naive T-cells, effector ...

As tissue-resident macrophages of the central nervous system parenchyma, microglia perform diverse essential functions during homeostasis and perturbations1. They primarily interact with neurons by means of synaptic engulfment and through the rapid elimination of apoptotic cells and non-functional synapses2. Here, by combining unbiased lipidomics and high-resolution spatial lipid imaging, deep single-cell transcriptome analysis and novel cell-type-specific mutants, we identified a previously ...

Single-cell studies have revealed substantial microglial diversity in development, homeostasis and disease. However, a framework enabling comparison and stratification of microglial states across contexts is needed. Here we generated an atlas of myeloid cell states by single-cell RNA sequencing more than one million central nervous system cells from more than 30 physiological and pathological conditions. This atlas enables us to establish a comprehensive taxonomy of myeloid cell states across ...

Compartmentalized inflammation is a key driver of multiple sclerosis (MS) progression, but the mechanisms sustaining its persistence remain unclear. A hallmark of this persistent and slowly evolving inflammatory process is chronic active MS lesions. We generated a high-resolution, single-cell molecular and spatial atlas of such lesions by combining single-nucleus RNA sequencing (snRNA-seq) with multiplexed error-robust fluorescence in situ hybridization (MERFISH). Within lesion rims, we identified ...