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The full impact of APOE4 (apolipoprotein E4), the strongest genetic risk factor for Alzheimer's disease (AD), on neuronal and network function remains unclear, particularly during early preclinical stages of disease. Here we show that young APOE4 knockin (E4-KI) mice exhibit hippocampal region-specific network hyperexcitability that predicts later cognitive deficits. This early phenotype arises from cell-type-specific subpopulations of smaller, hyperexcitable neurons and is eliminated by...

Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the...

Postoperative delirium (POD) accelerates the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD) in elderly patients. Microglial metabolic reprogramming, a pivotal aspect of the immune-inflammatory response, modulates microglia-neuron interactions and postoperative cognitive function through microenvironmental alterations. Aberrant overexpression of RUVBL2 disrupts metabolic homeostasis, leading to stress granule (SG) aggregation and fibrosis. This study investigated the...

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Recent human genetic studies have highlighted the potential role of microglial genes and their regulatory functions in the pathogenesis of Alzheimer's disease (AD). The transcription factor PU.1 (encoded by SPI1) is expressed mainly in microglia in the central nervous system and has been reported to be a genetic risk factor for AD. However, the role of microglial SPI1 in AD etiology is still poorly understood. Here, we demonstrate that the selective deletion of Spi1 in microglia exacerbates...

Rapid advancements in single-cell RNA sequencing (scRNA-seq) technologies revealed the richness of myriad attributes encompassing cell identity. However, the complexity of the data hinders tasks focusing on a specific biological signal. To address this challenge, we introduce bioIB, a framework based on the information bottleneck method, designed to extract an interpretable compressed representation of scRNA-seq data, optimally informative with respect to a specific biological signal, such as...

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Cost-cutting move is expected to cause resignations and turmoil

Science advocates urge Congress to reject 2027 budget plan

Fission-powered space flight, a 60-year dream, would supercharge outer Solar System exploration

China reached long expected milestone in 2024

Neural damage at any level of the neuraxis can lead to urogenital dysfunction, involving the lower urinary tract (LUT) and/or the sexual organs. The LUT consists of the bladder and the urethra (plus the prostate in males); LUT dysfunction can manifest as an underactive bladder, leading to urinary retention, or as an overactive bladder, leading to urinary incontinence. Manifestations of sexual dysfunction include loss of libido and dysfunction of erection, ejaculation and orgasm. In this Review,...

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Adrenergic signalling is heavily implicated in human age-related disease and yet the potential for this neuroendocrine signalling pathway to modulate ageing has received little attention. Here, we use Drosophila melanogaster to test if adrenergic-like signalling can promote longevity by manipulating tyramine (TA) or octopamine (OA), the invertebrate equivalents of adrenergic hormones. Increased neuronal synthesis of TA boosts health and longevity in both sexes, whereas OA is marginally...