BIN1 suppresses glial response to plaques in mouse model of Alzheimer's disease.

Introduction: The BIN1 coding variant rs138047593 (K358R) is linked to Late-Onset Alzheimer's Disease (LOAD) via targeted exome sequencing.

Methods: To elucidate the functional consequences of this rare coding variant on brain amyloidosis and neuroinflammation, we generated BIN1 knock-in mice using CRISPR/Cas9 technology. These mice were subsequently bred with 5xFAD transgenic mice, which serve as a model for Alzheimer's pathology.

Erythropoietin re-wires cognition-associated transcriptional networks.

Recombinant human erythropoietin (rhEPO) has potent procognitive effects, likely hematopoiesis-independent, but underlying mechanisms and physiological role of brain-expressed EPO remained obscure. Here, we provide transcriptional hippocampal profiling of male mice treated with rhEPO. Based on ~108,000 single nuclei, we unmask multiple pyramidal lineages with their comprehensive molecular signatures.

Introducing the brain erythropoietin circle to explain adaptive brain hardware upgrade and improved performance.

Executive functions, learning, attention, and processing speed are imperative facets of cognitive performance, affected in neuropsychiatric disorders. In clinical studies on different patient groups, recombinant human (rh) erythropoietin (EPO) lastingly improved higher cognition and reduced brain matter loss. Correspondingly, rhEPO treatment of young rodents or EPO receptor (EPOR) overexpression in pyramidal neurons caused remarkable and enduring cognitive improvement, together with enhanced hippocampal long-term potentiation.

Brain erythropoietin fine-tunes a counterbalance between neurodifferentiation and microglia in the adult hippocampus.

In adult cornu ammonis hippocampi, erythropoietin (EPO) expression drives the differentiation of new neurons, independent of DNA synthesis, and increases dendritic spine density. This substantial brain hardware upgrade is part of a regulatory circle: during motor-cognitive challenge, neurons experience "functional" hypoxia, triggering neuronal EPO production, which in turn promotes improved performance. Here, we show an unexpected involvement of resident microglia.

CaMKIIα Expressing Neurons to Report Activity-Related Endogenous Hypoxia upon Motor-Cognitive Challenge.

We previously introduced the brain erythropoietin (EPO) circle as a model to explain the adaptive 'brain hardware upgrade' and enhanced performance. In this fundamental circle, brain cells, challenged by motor-cognitive tasks, experience functional hypoxia, triggering the expression of EPO among other genes. We attested hypoxic cells by a transgenic reporter approach under the ubiquitous CAG promoter, with Hif-1α oxygen-dependent degradation-domain (ODD) fused to CreERT2-recombinase.

Hippocampal neurons respond to brain activity with functional hypoxia.

Physical activity and cognitive challenge are established non-invasive methods to induce comprehensive brain activation and thereby improve global brain function including mood and emotional well-being in healthy subjects and in patients. However, the mechanisms underlying this experimental and clinical observation and broadly exploited therapeutic tool are still widely obscure. Here we show in the behaving brain that physiological (endogenous) hypoxia is likely a respective lead mechanism, regulating hippocampal plasticity via adaptive gene expression.

Genetically induced brain inflammation by deletion transiently benefits from microglia depletion.

Reduced expression of 2'-3'-cyclic nucleotide 3'-phosphodiesterase () in humans and mice causes white matter inflammation and catatonic signs. These consequences are experimentally alleviated by microglia ablation colony-stimulating factor 1 receptor (CSF1R) inhibition using PLX5622. Here we address for the first time preclinical topics crucial for translation, most importantly ) the comparison of 2 long-term PLX5622 applications (prevention and treatment) 1 treatment alone, ) the correlation of catatonic signs and executive dysfunction, ) the phenotype of leftover microglia evading depletion, and ) the role of intercellular interactions for efficient CSF1R inhibition.