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Analysis of GRK2 aggregation in the pathology of Alzheimer disease in animal models

1 day 3 hours ago
The G-protein-coupled receptor kinase 2 (GRK2) exerts essential functions in cell growth and survival. Searching for a connection between GRK2 and the neurodegenerative Alzheimer disease (AD), we find increased aggregated serine-670-phosphorylated GRK2 (phospho-S670-GRK2) in brains of AD mice and patients with dementia likely due to AD. Harmful phospho-S670-GRK2 aggregation is induced by two hallmark proteins of AD: beta-amyloid and the neurofibrillary-tangle-inducing, TAU-P301L. Aggregated...
Joshua Abd Alla

Sex-specific APOE4-dependent innate immunity regulates meningeal lymphatics, brain lipids, neuroinflammation, and cognition

1 day 3 hours ago
Sex and apolipoprotein E ε4 (APOE4) interact to alter the risk for Alzheimer's disease and other neurodegenerative disorders. Herein, we show sex-specific differences in immune activation and lymphatic function in the meningeal dura of humanized female and male mice expressing two alleles of APOE4 (E4/E4), when compared with their respective sex-matched E3/E3 controls. We also describe distinct effects of APOE4 on brain lipid composition and inflammation in females and males that were partially...
Nickoleta Delivanoglou

Microglia-mediated protection against Alzheimer's disease pathology and detrimental effects in white matter revealed by Ptpn6 deletion

1 day 3 hours ago
Genetic variants affecting microglia can cause early-onset neurodegeneration or elevate Alzheimer's disease risk. To nominate regulators of relevant signaling pathways, we developed a genome-wide CRISPR screen in primary macrophages focused on survival. We identified Ptpn6, which encodes the inhibitory phosphatase SHP-1, as a crucial regulator for macrophage survival under reduced CSF1R signaling conditions in vitro. Deletion of Ptpn6 from adult microglia in vivo enhanced survival and decreased...
Ainhoa Etxeberria

Analysis of GRK2 aggregation in the pathology of Alzheimer disease in animal models

1 day 3 hours ago
The G-protein-coupled receptor kinase 2 (GRK2) exerts essential functions in cell growth and survival. Searching for a connection between GRK2 and the neurodegenerative Alzheimer disease (AD), we find increased aggregated serine-670-phosphorylated GRK2 (phospho-S670-GRK2) in brains of AD mice and patients with dementia likely due to AD. Harmful phospho-S670-GRK2 aggregation is induced by two hallmark proteins of AD: beta-amyloid and the neurofibrillary-tangle-inducing, TAU-P301L. Aggregated...
Joshua Abd Alla

Survival implications of BMI in nonagenarians and centenarians of the CEPH aging cohort

1 day 3 hours ago
As global life expectancy rises, understanding predictors of survival in extreme old age is crucial. Body mass index (BMI) is a widely used proxy for adiposity and nutritional status. In adults, a BMI between 18.5 and 24.9 kg/m² is considered healthy and associated with better life expectancy; yet in nonagenarians and centenarians it remains unclear whether this BMI range is ideal due to age-related physiological changes. We examined BMI and mortality associations in 780 adults aged ≥90 years...
Nasreddine Rajoua

MicroRNA-128-3p Deficiency Alleviates Bone Loss in Age-Related Osteoporosis via Activation of Canonical Wnt Signaling

1 day 3 hours ago
MicroRNA-128-3p (miR-128-3p) has emerged as a crucial regulator of the aging process and age-associated disorders. Recent research highlights the vital role of miR-128-3p in osteoclast (OC) differentiation and the progression of osteoporosis following ovariectomy. Nonetheless, the mechanism by which miR-128-3p influences osteoblast (OB)-mediated bone formation and contributes to bone loss associated with aging is poorly understood. The present investigation began with an analysis of human bone...
Gengyang Shen

Clinically relevant stereochemistry reprograms amyloid proteome for aggregation cross-talk-conferred neuroprotection

1 day 3 hours ago
The stereochemical diversity of Aβ42 in the brains of patients with Alzheimer's disease (AD) is a clinically recognized but poorly understood phenomenon. A critical gap in our knowledge is how the complex mixture of these stereoisomers collectively influences the aggregation pathway and neurotoxicity of Aβ42 at the molecular level. Drawing from stereoproteome data from AD patient brain tissues and previous studies, we engineered a panel of stereoisomers to more simply simulate the stereochemical...
Jiaxin Zhou

Correspondence of large-scale functional brain network decline across aging mice and humans

1 day 3 hours ago
Human aging is marked by progressive reorganization of large-scale functional brain networks; these brain network changes have been linked to cognitive decline and disease vulnerability. Conversely, while mice have served as powerful models for understanding the molecular and cellular changes that occur over the lifespan, an absence of precise characterization of age-related changes in large-scale functional brain network organization has limited cross-species translational insights. Here, using...
Ezra Winter-Nelson

Reversible aggregation-redispersion of Cu sites in Cu/CeO<sub>2</sub> catalysts with unlocked hydrogenation activity

1 day 3 hours ago
For oxide-supported metal catalysts, metal-support interaction (MSI) facilitates metal dispersion at the expense of the metallic character, resulting in a trade-off between active site utilization and intrinsic activity. Here, we used a thermal aging strategy to modulate the MSI in Cu/CeO(2) catalysts, facilitating the formation of metallic Cu sites upon H(2) reduction while maintaining metal dispersion. Systematic experiments confirmed that thermal aging at 800°C lowered the reduction...
Yu Zhang

Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders

1 day 3 hours ago
Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca^(2+) dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca^(2+) signalling pathways...
Maria V Sanchez-Mico

Generation of proliferative hESC-derived grape-clustered hepatocyte organoids with multipolar architecture as regenerative counterpart via synergy of YAP and IGF2 pathways

1 day 3 hours ago
Primary human hepatocyte (PHH)-derived organoids form grape-like clusters with proliferative capacity, hepatocyte functionality, and multipolar polarity, serving as valuable models for liver biology and therapeutics. However, deriving comparable organoids from human embryonic stem cells (hESCs) remains difficult. Here, we established a defined system to differentiate hESC-derived hepatoblast organoids into hepatocyte organoids (heporgs) with two morphologies: spheroid-like (S-heporgs) and...
Haibin Wu

Acquisitive plants exhibit stronger phenological shifts in response to warming: insights from meta-analysis and long-term monitoring

1 day 3 hours ago
As climate warming accelerates, shifts in plant phenology are reshaping the functioning and stability of terrestrial ecosystems. While the roles of climatic drivers in shaping phenological responses to warming are well established, the influence of intrinsic plant functional traits remains poorly understood. Here, we combine two complementary approaches through a meta-analysis of 124 field warming experiments and an analysis of long-term phenological monitoring networks (CPON and USA‑NPN) to...
Kexin Xiong

Role of dysregulated calcium homeostasis in astrocytes in neurodegenerative disorders

1 day 3 hours ago
Calcium signalling in astrocytes is a fundamental mechanism for maintaining brain homeostasis, shaping neuronal activity, and coordinating vascular and immune responses. Once considered secondary to neuronal signalling, astrocytic Ca^(2+) dynamics are now recognized as highly versatile, spatially compartmentalized and essential for regulating neurotransmitter uptake, ion buffering, metabolic support and mitochondrial function. Accumulating evidence shows that these Ca^(2+) signalling pathways...
Maria V Sanchez-Mico

Metabolomic signatures of extreme old age: findings from the New England Centenarian Study

1 day 3 hours ago
The New England Centenarian Study (NECS) provides a unique resource for the study of extreme human longevity (EL). To gain insight into biological pathways related to EL, chronological age and survival, we used an untargeted serum metabolomic approach (> 1400 metabolites) in 213 NECS participants, followed by integration of our findings with metabolomic data from four additional studies. Compared to their offspring and matched controls, EL individuals exhibited a distinct metabolic profile...
Stefano Monti