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Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration 1 . The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus 2 – 4 , yet little is known about the factors and mechanisms that mediate these effects. Here we show that ‘runner plasma’, collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation. Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer’s disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise. Plasma from voluntarily running mice reduces baseline expression of neuroinflammatory genes and experimentally induced brain inflammation when infused into sedentary mice.

Glioblastoma (GBM) is composed of heterogeneous tumor cell populations, including those with stem cell properties, termed glioma stem cells (GSCs). GSCs are innately less radiation sensitive than the tumor bulk and are believed to drive GBM formation and recurrence after repeated irradiation. However, it is unclear how GSCs adapt to escape the toxicity of repeated irradiation used in clinical practice. To identify important mediators of adaptive radioresistance in GBM, we generated radioresistant human and mouse GSCs by exposing them to repeat cycles of irradiation. Surviving subpopulations acquired strong radioresistance in vivo, which was accompanied by a reduction in cell proliferation and an increase in cell-cell adhesion and N-cadherin expression. Increasing N-cadherin expression rendered parental GSCs radioresistant, reduced their proliferation, and increased their stemness and intercellular adhesive properties. Conversely, radioresistant GSCs lost their acquired phenotypes upon CRISPR/Cas9-mediated knockout of N-cadherin. Mechanistically, elevated N-cadherin expression resulted in the accumulation of β-catenin at the cell surface, which suppressed Wnt/β-catenin proliferative signaling, reduced neural differentiation, and protected against apoptosis through Clusterin secretion. N-cadherin upregulation was induced by radiation-induced IGF1 secretion, and the radiation resistance phenotype could be reverted with picropodophyllin, a clinically applicable blood-brain-barrier permeable IGF1 receptor inhibitor, supporting clinical translation.

Tumors initiate by mutations in cancer cells, and progress through interactions of the cancer cells with non-malignant cells of the tumor microenvironment. Major players in the tumor microenvironment are cancer-associated fibroblasts (CAFs), which support tumor malignancy, and comprise up to 90% of the tumor mass in pancreatic cancer. CAFs are transcriptionally rewired by cancer cells. Whether this rewiring is differentially affected by different mutations in cancer cells is largely unknown. Here we address this question by dissecting the stromal landscape of BRCA -mutated and BRCA Wild-type pancreatic ductal adenocarcinoma. We comprehensively analyze pancreatic cancer samples from 42 patients, revealing different CAF subtype compositions in germline BRCA -mutated vs. BRCA Wild-type tumors. In particular, we detect an increase in a subset of immune-regulatory clusterin-positive CAFs in BRCA -mutated tumors. Using cancer organoids and mouse models we show that this process is mediated through activation of heat-shock factor 1, the transcriptional regulator of clusterin . Our findings unravel a dimension of stromal heterogeneity influenced by germline mutations in cancer cells, with direct implications for clinical research. Cancer-associated fibroblasts are transcriptionally rewired by signals from the cancer cells, resulting in heterogeneous populations. Here the authors show that loss of BRCA function in pancreatic cancer cells leads to HSF1–dependent accumulation of immune-regulatory clusterin-positive cancer associated fibroblasts.

Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity. Hepatokines are proteins secreted by the liver that can regulate whole body metabolism. Here the authors identify apolipoprotein J as a hepatokine that regulates muscle glucose metabolism and insulin resistance through a low-density lipoprotein receptor-related protein−2 mediated mechanism in mice.

Aims/hypothesis Diabetes is characterised by progressive loss of functional pancreatic beta cells. None of the therapeutic agents used to treat diabetes arrest this process; preventing beta cell loss remains a major unmet need. We have previously shown that serum from eight young healthy male participants who exercised for 8 weeks protected human islets and insulin-producing EndoC-βH1 cells from apoptosis induced by proinflammatory cytokines or the endoplasmic reticulum (ER) stressor thapsigargin. Whether this protective effect is influenced by sex, age, training modality, ancestry or diabetes is unknown. Methods We enrolled 82 individuals, male or female, non-diabetic or diabetic, from different origins, in different supervised training protocols for 8–12 weeks (including training at home during the COVID-19 pandemic). EndoC-βH1 cells were treated with ‘exercised’ serum or with the exerkine clusterin to ascertain cytoprotection from ER stress. Results The exercise interventions were effective and improved V ̇ O 2 peak values in both younger and older, non-obese and obese, non-diabetic and diabetic participants. Serum obtained after training conferred significant beta cell protection (28% to 35% protection after 4 and 8 weeks of training, respectively) from severe ER stress-induced apoptosis. Cytoprotection was not affected by the type of exercise training or participant age, sex, BMI or ancestry, and persisted for up to 2 months after the end of the training programme. Serum from exercised participants with type 1 or type 2 diabetes was similarly protective. Clusterin reproduced the beneficial effects of exercised sera. Conclusions/interpretation These data uncover the unexpected potential to preserve beta cell health by exercise training, opening a new avenue to prevent or slow diabetes progression through humoral muscle–beta cell crosstalk. Graphical abstract

Background Genome-wide association studies have established clusterin (CLU) as a genetic modifier for late-onset Alzheimer’s disease (AD). Both protective and risk alleles have been identified which may be associated with its expression levels. However, the physiological function of clusterin in the central nervous system remains largely unknown. Methods We examined Clu expression in mouse brains by immunohistochemistry and high-resolution imaging. We performed electrophysiological recordings and morphological analysis of dendritic spines in wild-type and Clu knockout mice. We tested synaptic function of astrocytic Clu using neuron-glia co-cultures and by AAV-mediated astroglial Clu expression in vivo. Finally, we investigated the role of astrocytic Clu on synaptic properties and amyloid pathology in 5xFAD transgenic mouse model of AD. Results We show that astrocyte secreted Clu co-localizes with presynaptic puncta of excitatory neurons. Loss of Clu led to impaired presynaptic function and reduced spine density in vivo. Neurons co-cultured with Clu-overexpressing astrocytes or treated with conditioned media from HEK293 cells transfected with Clu displayed enhanced excitatory neurotransmission. AAV-mediated astroglial Clu expression promoted excitatory neurotransmission in wild-type mice and rescued synaptic deficits in Clu knockout mice. Overexpression of Clu in the astrocytes of 5xFAD mice led to reduced Aβ pathology and fully rescued the synaptic deficits. Conclusion We identify Clu as an astrocyte-derived synaptogenic and anti-amyloid factor; the combination of these activities may influence the progression of late-onset AD.

Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor belong to the low density lipoprotein receptor family and bind apolipoprotein E. These receptors interact with the clathrin machinery to mediate endocytosis of macromolecules but also interact with other adapter proteins to perform as signal transduction receptors. The best characterized signaling pathway in which ApoER2 and VLDL receptor (VLDLR) are involved is the Reelin pathway. This pathway plays a pivotal role in the development of laminated structures of the brain and in synaptic plasticity of the adult brain. Since Reelin and apolipoprotein E, are ligands of ApoER2 and VLDLR, these receptors are of interest with respect to Alzheimer’s disease. We will focus this review on the complex structure of ApoER2 and VLDLR and a recently characterized ligand, namely clusterin.

Chronic pressure overload induces adverse cardiac remodelling characterised by left ventricular (LV) hypertrophy and fibrosis, leading to heart failure (HF). Identification of new biomarkers for adverse cardiac remodelling enables us to better understand this process and, consequently, to prevent HF. We recently identified clusterin (CLU) as a biomarker of cardiac remodelling and HF after myocardial infarction. The aim of this study was to investigate whether CLU expression is regulated in the heart and could be used as an indicator of adverse cardiac remodelling in response to pressure overload. We quantified CLU in the LV of mice subjected to transverse aortic constriction (TAC) and observed increased CLU mRNA levels and its mature protein form (m‐CLU) compared to the sham. Interestingly, CLU mRNA levels were positively correlated with pro‐hypertrophic (ANP, BNP, B‐MHC), pro‐ and anti‐fibrotic (TGFb, ColI and CILP) genes. In addition, m‐CLU was positively correlated with LV hypertrophy, LV end diastolic and systolic diameters, and negatively correlated with LV ejection fraction. Finally, we observed that m‐CLU levels only increased in TAC mice with severe cardiac remodelling and dysfunction without any significant difference in plasma CLU levels. This is the first study to demonstrate that cardiac expression of CLU is induced in the LV of TAC mice during adverse cardiac remodelling. However, plasma CLU levels could not be used as biomarkers of TAC‐induced cardiac remodelling and dysfunction.

Although the mechanism of Aβ action in the pathogenesis of Alzheimer’s disease (AD) has remained elusive, it is known to increase the expression of the antagonist of canonical wnt signalling, Dickkopf-1 (Dkk1), whereas the silencing of Dkk1 blocks Aβ neurotoxicity. We asked if clusterin, known to be regulated by wnt, is part of an Aβ/Dkk1 neurotoxic pathway. Knockdown of clusterin in primary neurons reduced Aβ toxicity and DKK1 upregulation and, conversely, Aβ increased intracellular clusterin and decreased clusterin protein secretion, resulting in the p53-dependent induction of DKK1 . To further elucidate how the clusterin-dependent induction of Dkk1 by Aβ mediates neurotoxicity, we measured the effects of Aβ and Dkk1 protein on whole-genome expression in primary neurons, finding a common pathway suggestive of activation of wnt–planar cell polarity (PCP)–c-Jun N-terminal kinase (JNK) signalling leading to the induction of genes including EGR1 (early growth response-1), NAB2 (Ngfi-A-binding protein-2) and KLF10 (Krüppel-like factor-10) that, when individually silenced, protected against Aβ neurotoxicity and/or tau phosphorylation. Neuronal overexpression of Dkk1 in transgenic mice mimicked this Aβ-induced pathway and resulted in age-dependent increases in tau phosphorylation in hippocampus and cognitive impairment. Furthermore, we show that this Dkk1/wnt–PCP–JNK pathway is active in an Aβ-based mouse model of AD and in AD brain, but not in a tau-based mouse model or in frontotemporal dementia brain. Thus, we have identified a pathway whereby Aβ induces a clusterin/p53/Dkk1/wnt–PCP–JNK pathway, which drives the upregulation of several genes that mediate the development of AD-like neuropathologies, thereby providing new mechanistic insights into the action of Aβ in neurodegenerative diseases.

This study aimed to examine, a multifaceted chaperon-like protein exerting anti-inflammatory action, clusterin (CLU), mRNA and protein levels in the systemic and local joint environment of knee osteoarthritis (OA) patients and to determine whether CLU inhibited interleukin (IL)-1β-induced inflammation in knee OA fibroblast-like synoviocytes (FLSs) through modulating phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. CLU protein and mRNA expressions in the synovium and its protein levels in plasma and synovial fluid of knee OA patients were measured using immunohistochemistry, real-time PCR, and ELISA, respectively. Anti-inflammatory effect of CLU was further elucidated in knee OA FLSs treated with IL-1β in the absence or presence of CLU, CLU alone, or PI3K inhibitor (LY294002) along with IL-1β and CLU. In a clinical study, compared with knee OA patients without synovitis, CLU protein and mRNA were expressed in the synovium of knee OA patients with synovitis, especially those with high-grade, consistent with analyses of its plasma and synovial fluid levels. CLU mRNA and protein levels were both associated with synovitis severity. An in vitro study uncovered that CLU significantly alleviated IL-1β-induced overproduction of nitric oxide and IL-6 in knee OA FLSs. Furthermore, CLU significantly attenuated inflammation and extracellular matrix degradation induced by IL-1β via down-regulating expressions of IL-6 , nuclear factor kappa B, and matrix metalloproteinase-13. Mechanistically, CLU significantly impeded IL-1β-induced Akt phosphorylation in knee OA FLSs, in line with addition of LY294002 along with IL-1β and CLU. These findings suggest that CLU may have potential as a novel therapeutic target for synovitis and cartilage destruction in knee OA.