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The taurine transporter (TAUT) mediates cellular taurine uptake, playing a critical role in human health and longevity. In this study, we present cryogenic electron microscopy structures of both mouse and human TAUT in various conformational states. The taurine-bound, occluded forms of mouse and human TAUT reveal the substrate binding pocket and the ion binding sites. The amino group of taurine interacts with Glu406 at the binding site, constituting a key structural feature determining substrate...

The morphological features of particles, notably shape anisotropy, critically influence the rheological properties of dense suspensions, spanning both natural and engineered systems. This work explores the potential of using shape memory particles to dynamically regulate suspension fluid flow through controllable shape transformations. First, we synthesize shape-memory particles with programmable anisotropy from liquid crystal elastomers, such that the stiffness and shapes of the particles can...

The exploration for safe, effective intervention strategies to improve longevity and aging-related diseases is attracting attention to prolong the healthy lifespan. Since aging is based on cellular changes, including telomere attrition, DNA damage, and mitochondrial dysfunction, therapies related to stem cells are expected to be a rational strategy for solving aging problems at the cellular level. Mesenchymal stem cells (MSCs) are an easily accessible, safe candidate, as they supply paracrine...

Canagliflozin (Cana) started at 16 months of age and 16-hydroxy-estradiol (OH_Est) started at 12 months each led to significant increases in lifespan in male UM-HET3 mice but significant decreases in female lifespan. To seek insights into the basis for these sex-specific effects, we performed end-of-life histopathological analyses of control and treated mice for all three interventions testing program sites. There were no significant drug-induced alterations in inferred cause of death, although...

The current depth of site-specific N-glycoproteomics is insufficient to fully characterize glycosylation events in biological samples. Herein, we achieve an ultradeep and precision analysis of the N-glycoproteome of mouse tissues by integrating multiple workflows. The largest N-glycoproteomic dataset to date is established on mice, which contains 91,972 precursor glycopeptides, 62,216 glycoforms, 8939 glycosites and 4563 glycoproteins. The database consists of 6.8 million glyco-spectra...

Proteases recognize substrates by decoding sequence information-an essential cellular process elusive when recognition motifs are absent. Here, we unravel this problem for γ-secretase, an intramembrane-cleaving protease associated with Alzheimer's disease and cancer, by developing Comparative Physicochemical Profiling (CPP), a sequence-based algorithm for identifying interpretable physicochemical features. We show that CPP deciphers a γ-secretase substrate signature with single-residue...

Parkinson disease (PD) is a heterogeneous syndrome. There is a need for biology-driven subtyping to inform specific therapeutic strategies. In a two-center study with de novo and established PD cohorts, we use vesicular acetylcholine transporter ligand [^(18)F]FEOBV brain PET to assess cholinergic systems changes in early to moderate PD. Principal component analysis (PCA) is applied to data from 245 PD subjects to define cholinergic subgroups at baseline. Three PD subgroups are identified:...

Circulating blood factors are critical for homeostasis of the adult ventricular-subventricular (V-SVZ) and subgranular zones, which contain neural stem cells (NSCs) crucial for sustained neurogenesis. Circulating sphingosine-1-phosphate (S1P) bound to apolipoprotein M (ApoM), a principal component of high-density lipoproteins, is involved in various biological processes, but its role in neurogenic niches is poorly understood. Herein, using Apom^(-/-) mice, we show that blood ApoM-S1P deficiency...

The self-assembly of biomolecules through noncovalent interactions is critical in both physiological and pathological processes, as exemplified by the assembly of amyloid β peptide (Aβ) into oligomers or fibrils in Alzheimer's disease (AD). Developing molecules that can modulate this assembly process holds significant mechanistic and therapeutic potential. In this study, we identified glycopeptides as a class of protein aggregation modulators, showing that β-N-acetylgalactosamine...

Previous studies suggest glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD), but the link between their markers and synaptic abnormalities in the living brain remains unclear. We investigated the association between glial reactivity and synaptic dysfunction biomarkers in cerebrospinal fluid (CSF) from 478 individuals in cognitively unimpaired (CU) and cognitively impaired (CI) individuals. We measured amyloid-β (Aβ), phosphorylated tau (pTau181), astrocyte...

Smelling is a human sense, expressing strong sexual dimorphisms. We aim to improve the knowledge of the genetics of human olfactory perception by performing an exploratory genome-wide association meta-analysis of up to 21,495 individuals of European ancestry. By sex-stratified and overall analysis of the identification of twelve odours and an identification score, we discovered ten independent loci, seven of them novel, with trait-wise genome-wide significance (p < 5 × 10^(-8)) involving five...

To understand how aging affects functional decline and increases disease risk, it is necessary to develop measures of how fast a person is aging. Using data from the Dunedin Study, we introduce an accurate and reliable measure for the rate of longitudinal aging derived from cross-sectional brain magnetic resonance imaging, that is, the Dunedin Pace of Aging Calculated from NeuroImaging (DunedinPACNI). Exporting this measure to the Alzheimer's Disease Neuroimaging Initiative, UK Biobank and...

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The canonical Alzheimer's Disease (AD) pathological cascade posits that the accumulation of amyloid beta (Aβ) is the initiating event, accelerating the accumulation of tau in the entorhinal cortex (EC), which subsequently spreads into the neocortex. Here in a multi-cohort study (ADNI, A4, HABS-HD) of 1354 participants with multimodal imaging and genetic information we queried how genetic variation affects these stages of the AD cascade. We observed that females and APOE-ε4 homozygotes are more...

While deep brain stimulation (DBS) remains an effective therapy for Parkinson's disease (PD), sources of variance in patient outcomes are still not fully understood, underscoring a need for better prognostic criteria. Here, we leveraged routinely collected T1-weighted (T1-w) magnetic resonance imaging (MRI) data to derive patient-specific measures of brain structure and evaluate their usefulness in predicting changes in PD medications in response to DBS. Preoperative T1-w MRI data from 231...

Extracellular vesicles (EVs) in plasma are composed of exosomes, microvesicles, and apoptotic bodies. We report a plasma EV enrichment strategy using magnetic beads called Mag-Net. Proteomic interrogation of this plasma EV fraction enables the detection of proteins that are beyond the dynamic range of liquid chromatography-mass spectrometry of unfractionated plasma. Mag-Net is robust, reproducible, inexpensive, and requires <100 μL plasma input. Coupled to data-independent mass spectrometry, we...

Alzheimer's disease (AD), the leading cause of senile dementia, lacks effective therapies. While microglia are central to AD pathology, key therapeutic targets remain unclear. Here we identify microglial connexin43 (Cx43) hemichannels as a regulator of microglial reactivity in AD, positioning them as a promising therapeutic target. Post-mortem AD patient tissue showed elevated Cx43 levels in periplaque microglia. In the APP(swe)/PS1(dE9) (APP/PS1) mouse model of amyloidosis, we demonstrated that...

Almost all individuals with Down Syndrome (DS) develop Alzheimer's disease (AD) by mid to late life. However, the degree to which AD in DS shares pathological changes with sporadic late-onset AD (LOAD) and autosomal dominant AD (ADAD) beyond core AD biomarkers such as amyloid-β (Aβ) and tau is unknown. Here, we used proteomics of cerebrospinal fluid from individuals with DS (n = 229) in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort to assess the evolution of AD...

Neuronal senescence (i.e., neurescence) is an important hallmark of aging and neurodegeneration, but it remains poorly characterized in the human brain due to the lack of reliable markers. This study aimed to identify neurescence markers based on single-nucleus transcriptome data from postmortem human prefrontal cortex. Using an eigengene approach, we integrated three gene panels: (a) SenMayo, (b) canonical senescence pathway (CSP), and (c) senescence initiating pathway (SIP), to identify...

Cellular senescence is a key driver of heart disease, yet its regulation in cardiomyocytes remains poorly understood. Selenoprotein T (SELENOT) plays a crucial role in cardiomyocyte differentiation and protection, but its role in cardiomyocyte senescence remains unknown. Here, we explore the novel role of SELENOT in preserving cardiomyocyte viability and genomic integrity during doxorubicin-induced senescence. Senescent differentiated cardiomyocytes exhibit hallmarks of cellular senescence,...