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The burden of a gene
A variant called APOE4 is notorious for its link to Alzheimer's. Can new insights into its function help stave off disease?
Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics
The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14...
Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP
Microtubule-associated protein tau (MAPT/tau) accumulates in a family of neurodegenerative diseases, including Alzheimer's disease (AD). In disease, tau is aberrantly modified by post-translational modifications (PTMs), including hyper-phosphorylation. However, it is often unclear which of these PTMs contribute to tau's accumulation or what mechanisms might be involved. To explore these questions, we focus on a cleaved proteoform of tau (tauC3), which selectively accumulates in AD and was...
Clearance and transport of amyloid beta by peripheral monocytes correlate with Alzheimer's disease progression
Impaired clearance of amyloid β (Aβ) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aβ clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aβ-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes...
Profiling the fecal microbiome and its modulators across the lifespan in the Netherlands
Defining what constitutes a healthy microbiome throughout our lives remains an ongoing challenge. Understanding to what extent host and environmental factors can influence it has been the primary motivation for large population studies worldwide. Here, we describe the fecal microbiome of 3,746 individuals (0-87 years of age) in a nationwide study in the Netherlands, in association with extensive questionnaires. We validate previous findings, such as infant-adult trajectories, and explore the...
Hunt for longevity drugs gets new life
Decades-old project has new funding and a new set of compounds to test.
Transiently formed nucleus-to-cilium microtubule arrays mediate senescence initiation in a KIFC3-dependent manner
Despite the importance of cellular senescence in human health, how damaged cells undergo senescence remains elusive. We have previously shown that promyelocytic leukemia nuclear body (PML-NBs) translocation of the ciliary FBF1 is essential for senescence induction in stressed cells. Here we discover that an early cellular event occurring in stressed cells is the transient assembly of stress-induced nucleus-to-cilium microtubule arrays (sinc-MTs). The sinc-MTs are distinguished by unusual...
Nuclear lamin A/C phosphorylation by loss of androgen receptor leads to cancer-associated fibroblast activation
Alterations in nuclear structure and function are hallmarks of cancer cells. Little is known about these changes in Cancer-Associated Fibroblasts (CAFs), crucial components of the tumor microenvironment. Loss of the androgen receptor (AR) in human dermal fibroblasts (HDFs), which triggers early steps of CAF activation, leads to nuclear membrane changes and micronuclei formation, independent of cellular senescence. Similar changes occur in established CAFs and are reversed by restoring AR...
DOR activation in mature oligodendrocytes regulates α-ketoglutarate metabolism leading to enhanced remyelination in aged mice
The decreased ability of mature oligodendrocytes to produce myelin negatively affects remyelination in demyelinating diseases and aging, but the underlying mechanisms are incompletely understood. In the present study, we identify a mature oligodendrocyte-enriched transcriptional coregulator diabetes- and obesity-related gene (DOR)/tumor protein p53-inducible nuclear protein 2 (TP53INP2), downregulated in demyelinated lesions of donors with multiple sclerosis and in aged oligodendrocyte-lineage...
The brain aged more slowly in monkeys given a cheap diabetes drug
No abstract
Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence
The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified...
Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence
Post-2030 global goals need explicit targets for cities and businesses
Science, Volume 385, Issue 6714, September 2024.
Offsets, carbon markets, and climate and economic justice
Science, Volume 385, Issue 6714, September 2024.
Erratum for the Research Article “Where and with whom does a brief social-belonging intervention promote progress in college?” by G. M. Walton et al.
Science, Volume 385, Issue 6714, September 2024.