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Alzheimer's disease (AD) remains the leading cause of dementia worldwide and an escalating global health crisis. The hallmark amyloid plaques and neurofibrillary tangles (NFT) are now known to be accompanied by a complex array of pathologies that culminate in neurodegeneration and cognitive decline. New disease-modifying therapies for AD can now slow cognitive decline through the removal of amyloid plaques from the brain, but treatments to stop or prevent cognitive impairment remain elusive. In...

Parkinson's disease (PD) is characterized by progressive loss of nigral dopaminergic neurons, resulting in disabling motor symptoms. Intracerebral transplantation of stem cell-derived dopaminergic progenitors to replace lost endogenous dopaminergic neurons offers a new potentially restorative therapeutic approach for PD. Here we report the 12-month primary safety end point and interim efficacy outcomes from a phase 1/2, open-label, multicenter trial evaluating STEM-PD, a cryopreserved,...

While spatial multiomics offers insights into complex biological systems, its widespread adoption is hindered by technical challenges, specialized requirements and limited accessibility. Here we present NicheTrans, a spatially aware cross-omics translation method and a flexible Transformer-based multimodal framework. Unlike existing single-cell translation methods, NicheTrans incorporates both cellular microenvironment information and multimodal data. We validated the advantage of NicheTrans...

Complement component 1q (C1q), the initiator of the classical complement cascade, mediates synaptic elimination in development and disease, yet the triggers for its deposition on synapses remain unclear. Using in vivo chemogenetics, we demonstrate that neuronal hyperactivity induces region-specific, C1q-dependent synapse loss in the adult hippocampus. Suppressing perforant pathway hyperactivity in a mouse model of Alzheimer's disease reduced local amyloid-β amounts and C1q deposition and...

Polycrystalline ice formation concentrates mineral nanoparticles into liquid boundaries between growing ice crystals. Here we show that minutes of freezing dictate iron mineral fate over subsequent months of aqueous aging. A single freeze-thaw cycle irreversibly aggregates ferrihydrite through converging physical and chemical mechanisms. Freeze concentration collapses electrostatic barriers while cryosuction strips hydration layers and compresses nanoparticles into micrometer-scale planar...

Disruption of proteostasis is a hallmark of aging. Given that cellular resources are limited, this necessitates a coordinated orchestration of different proteostatic subsystems. Yet, the principles governing this process, including the potential role of trade-offs, are not well defined. Here, we report a trade-off between the endoplasmic reticulum unfolded protein response (UPR^(ER)) and the cytosolic UPR (UPR^(cyto)) in C. elegans that influences lifespan. We find that wild-type animals...

DNA methylation-based epigenetic clocks have been highlighted as promising biomarkers of ageing, and they have been shown to robustly predict morbidity and mortality. However, current literature is lacking a formal analysis of the increased prediction accuracy, or the added value, of the epigenetic clocks over traditional risk factors, such as body composition, smoking, or alcohol consumption, in predicting common chronic diseases. Here, we have compared the most commonly used epigenetic clocks...

Aging is accompanied by widespread remodeling of DNA methylation (DNAm), which can be leveraged to build epigenetic clocks. In mice, most DNAm clocks rely on internal organs or terminal tissues, limiting longitudinal studies. Here, we compared age-associated DNAm patterns in matched blood and tail-an easily accessible but underexplored tissue-and evaluated both as substrates for tissue-specific DNAm age prediction. Matched blood and tail were collected from male C57BL/6N Per2::Luc mice aged...

Repressor Element 1-Silencing Transcription factor (REST) emerges as a metabolism-sensitive transcriptional hub that supports basal mitophagy, mitochondrial quality, and synaptic function in neurons. In Alzheimer's disease, REST becomes mislocalized and functionally impaired, coinciding with early defects in mitochondrial quality control. Activation of the NAD^(+) -SIRT1 axis enhances REST nuclear activity, restores its mitochondrial and neuroprotective gene programs, and attenuates pathological...

CONCLUSIONS: The UMNs of the older adults and the potential threat to inequalities require the attention of policymakers. Interventions should focus on improving access to medical services, with a particular emphasis on addressing the needs of vulnerable populations.

No abstract

The incidence of neurodegenerative diseases, including Alzheimer's disease (AD), continues to increase with the extension of human lifespan. However, their pathogenesis remains incompletely understood. Altered energy metabolism, particularly glucose metabolism involving glycolysis and oxidative phosphorylation, is widely recognized as an early pathological feature of neurodegenerative diseases. Astrocytes, the most numerous and widely distributed functional cells in the central nervous system...

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