Biology subjects

Anink, J.

Publications and source records attributed to Anink, J..

4 recordsLinked to original sources

bioRxiv2025

Unique transcriptional profiles of adult human immature neurons in healthy aging, Alzheimer's disease, and cognitive resilience

The existence and functional significance of immature neurons in the adult human brain, particularly in the context of neurodegenerative disorders, remain controversial. While rodent studies have highlighted active roles for adult-born immature neurons in the hippocampus under both healthy conditions and in Alzheimers disease (AD), evidence from the human brain is limited and lacks detailed molecular characterization. To address this gap, we performed single-nucleus RNA sequencing in aged healthy, AD and dementia-resilient human hippocampus to probe immature neuronal signatures and gene expression alterations associated with AD pathology and resilience. Employing a novel experimental and computational pipeline, we identified persistent populations of immature neurons across all donor groups, with transcriptional profiles distinct from both fetal counterparts and adult mature hippocampal neurons. These profiles were associated with juvenile cellular functions, suggesting that the presence of these immature neuronal populations per se may actively contribute to maintaining homeostasis within the aged human hippocampus, a role that may be disrupted in AD. In the resilient brain, immature neurons were involved in transcriptional programs and intercellular interactions associated with anti-inflammatory, neurotrophic, neuroprotective, myelinating, anti-apoptotic and anti-amyloidogenic signaling pathways, suggesting active roles for the immature cells in enhancing cognitive resilience in the presence of AD pathology. Our findings reveal novel, putative physiological roles for immature neurons in the healthy and resilient adult human brain, and offer a resource for probing new strategies with potential functional relevance in AD.

neuroscience↗

bioRxiv2024

Single-cell profiling of cortical tubers in tuberous sclerosis complex shows molecular structure preservation and massive reorganization of metabolism

Tuberous sclerosis complex (TSC) is a multisystemic genetic disorder associated with loss-of-function mutations in the TSC1 or TSC2 gene, which lead mTOR pathway hyperactivation and epileptogenesis. Cortical tubers are the hallmark of TSC and represent disorganized cortical structure underlying the generation of focal seizures. Here, we report single-nucleus RNA sequencing in resected cortical tubers vs matched pediatric controls. Strikingly, in spite of severe cortical disorganization, we found that cortical tubers preserve all neuronal subtypes, even the rarest ones. Moreover, we showed that principal neurons largely preserve spatial position based on transcriptional signatures. Principal neurons and layer 1-2 GABAergic neurons that modulate upper cortical circuits exhibited the largest gene expression changes. Interestingly, multiple mTOR pathway gene expression changes in TSC counteracted mTOR hyperactivation. TSC neuronal, but not glial, networks exhibited massive metabolic reorganization with a reduction in mitochondrial respiration and a concomitant switch to fatty acid metabolism. Finally, we show that neuron-specific AMPA receptor signaling might underlie epileptogenesis in TSC and could represent a potential candidate for therapeutic targeting.

neuroscience↗

bioRxiv2023

SorLA restricts TNFalpha release from microglia to shape glioma-supportive brain microenvironment

SorLA, encoded by the gene SORL1, is an intracellular sorting receptor of the VPS10P domain receptor gene family. Although SorLA is best recognized for its ability to shuttle target proteins between intracellular compartments in neurons, recent data suggest that also its microglial expression can be of high relevance for the pathogenesis of brain diseases, including glioblastoma (GBM). Here we interrogated the impact of SorLA on the functional properties of glioma-associated microglia and macrophages (GAMs). In the GBM microenvironment, GAMs are re-programmed and in turn lose the ability to elicit anti-tumor responses. Instead, they acquire glioma-supporting phenotype, which is a key mechanism promoting glioma progression. Our analysis of scRNA-seq data from GBM patients revealed that the pro-tumorigenic and pro-inflammatory properties of GAMs are linked to high and low SORL1 expression, respectively. Using cell models, we confirm that SorLA levels are differentially regulated by the presence of glioma cells and by inflammatory cues. We further show that SorLA acts as a sorting receptor for the pro-inflammatory cytokine TNF to restrain its secretion from microglia. As a consequence, loss of SorLA enhanced the pro-inflammatory potential of microglia, having a remarkable impact on glioma progression. In a murine model of glioma, SorLA-deficient mice develop smaller tumors and show hallmarks of anti-tumor response including altered microglia morphology, enhanced necroptosis, and massive neutrophil influx into the tumor parenchyma. Our findings indicate that SorLA is a key player in shaping the phenotype of GAMs, and its depletion can unlock an anti-tumor response. Significance statementOur study provides insight into the mechanisms shaping the tumor microenvironment in glioblastoma (GBM), the most prevalent and aggressive brain malignancy in adults. Poor prognosis in GBM largely results from the properties of the glioma milieu that blocks the anti-tumor response. We show that SorLA restricts release of the pro-inflammatory cytokine TNF from microglia, thereby hampering their anti-glioma response. SorLA depletion reinforces the pro-inflammatory properties of tumor microenvironment and inhibits glioma growth. These findings have significant implications for our understanding of glioma biology, indicating SorLA-TNF interaction as a potential target in GBM therapies. They also offer a new perspective on SorLA activities in microglia which emerge as highly relevant not only for the pathogenesis GBM, but also of other brain diseases such as Alzheimers disease.

neuroscience↗

bioRxiv2022

Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Microglial activation plays central roles in neuro-inflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells is unique to a subset of species within the Muroidea superfamily of rodents. We show that TSPO is mechanistically linked to classical pro-inflammatory myeloid cell function in rodents but not humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO PET reflects density of inflammatory cells rather than activation state.

neuroscience↗