Explore the vast range of titles available.

Monoclonal antibodies (mAbs) targeting immune checkpoint pathways such as programmed cell death protein 1 (PD‐1)/PD‐L1 are central to modern immunotherapy, yet scalable methods to assess their functional blockade remain limited. We present a bead‐based flow cytometry assay for quantifying the inhibition of PD‐1/PD‐L1 interaction by antibodies. Recombinant human PD‐1 protein was conjugated to polystyrene beads, and its interaction with recombinant human PD‐L1 protein labeled with a fluorochrome was measured. The inhibitory activity of an anti‐PD‐L1 mAb was quantified based on their ability to disrupt this interaction. The assay was validated for intra‐ and inter‐assay precision, in addition, functionality was confirmed using a T cell coculture assay. The assay demonstrated dose‐dependent inhibition by the αPD‐L1 mAb, with a calculated mean IC 50 of 3.122 µg/mL. The method proved to be reproducible for the determination of antibody blocking activity, with relative standard deviation (RSD) < 20% between three independent runs. At the concentration approximating the IC 50 detected on the bead assay, the antibody significantly restored CD69 expression on the T cell surface ( p = 0.0001) in a coculture in vitro system. In addition, the methodology could successfully distinguish the blocking capacity of two anti‐PD‐L1 antibodies with different affinities. This high‐throughput compatible platform offers a reliable tool for screening PD‐1/PD‐L1 blocking antibodies, supporting immunotherapy discovery and development.

Defective brain hormonal signaling has been associated with Alzheimer’s disease (AD), a disorder characterized by synapse and memory failure. Irisin is an exercise-induced myokine released on cleavage of the membrane-bound precursor protein fibronectin type III domain-containing protein 5 (FNDC5), also expressed in the hippocampus. Here we show that FNDC5/irisin levels are reduced in AD hippocampi and cerebrospinal fluid, and in experimental AD models. Knockdown of brain FNDC5/irisin impairs long-term potentiation and novel object recognition memory in mice. Conversely, boosting brain levels of FNDC5/irisin rescues synaptic plasticity and memory in AD mouse models. Peripheral overexpression of FNDC5/irisin rescues memory impairment, whereas blockade of either peripheral or brain FNDC5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice. By showing that FNDC5/irisin is an important mediator of the beneficial effects of exercise in AD models, our findings place FNDC5/irisin as a novel agent capable of opposing synapse failure and memory impairment in AD. Expression of the exercise-induced myokine irisin (FNDC5) is lower in patients with AD. Whereas knockdown of FNDC5/irisin is sufficient to induce learning and memory deficits, restoration of its expression can ameliorate these phenotypes in rodent models.

Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD‐associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α‐P). AβOs further induced eIF2α‐P and activated pro‐inflammatory IKKβ/NF‐κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor‐α (TNF‐α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD. Synopsis Centrally administered Aβ oligomers can trigger insulin resistance by engaging ER stress and inflammatory signals in the central nervous system. This study provides important insights into the link between Alzheimer's disease and diabetes by pointing to a common etiology. Aβ oligomers (ΑβOs), toxins that accumulate in the AD brain and have been linked to neuronal dysfunction in brain areas related to learning and memory, impact the hypothalamus of mice and macaques, revealing a novel toxic mechanism of AβOs in the brain. Infusion of AβOs in the brain triggers peripheral glucose intolerance, insulin resistance and other diabetes‐related metabolic alterations in mice. Similar metabolic alterations were verified in two transgenic mouse models of AD. Blockade of brain inflammation or ER stress attenuates peripheral glucose intolerance induced by brain infusion of AβOs, suggesting that AβOs use a central route to disrupt metabolic control in peripheral tissues. Current results may explain why AD patients have increased risk of developing diabetes, and suggest that targeting the hypothalamus may constitute an approach to combat peripheral metabolic deregulation in AD. Graphical Abstract Centrally administered Aβ oligomers can trigger insulin resistance by engaging ER stress and inflammatory signals in the central nervous system. This study provides important insights into the link between Alzheimer's disease and diabetes by pointing to a common etiology.