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Neurophysiological trajectories in Alzheimer's disease progression

22 hours 46 minutes ago
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the...
Kiwamu Kudo

Meta-Research: Understudied genes are lost in a leaky pipeline between genome-wide assays and reporting of results

22 hours 46 minutes ago
Present-day publications on human genes primarily feature genes that already appeared in many publications prior to completion of the Human Genome Project in 2003. These patterns persist despite the subsequent adoption of high-throughput technologies, which routinely identify novel genes associated with biological processes and disease. Although several hypotheses for bias in the selection of genes as research targets have been proposed, their explanatory powers have not yet been compared. Our...
Reese Richardson

voyAGEr, a free web interface for the analysis of age-related gene expression alterations in human tissues

22 hours 46 minutes ago
We herein introduce voyAGEr, an online graphical interface to explore age-related gene expression alterations in 49 human tissues. voyAGEr offers a visualisation and statistical toolkit for the finding and functional exploration of sex- and tissue-specific transcriptomic changes with age. In its conception, we developed a novel bioinformatics pipeline leveraging RNA sequencing data, from the GTEx project, encompassing more than 900 individuals. voyAGEr reveals transcriptomic signatures of the...
Arthur L Schneider

Meta-Research: Understudied genes are lost in a leaky pipeline between genome-wide assays and reporting of results

22 hours 46 minutes ago
Present-day publications on human genes primarily feature genes that already appeared in many publications prior to completion of the Human Genome Project in 2003. These patterns persist despite the subsequent adoption of high-throughput technologies, which routinely identify novel genes associated with biological processes and disease. Although several hypotheses for bias in the selection of genes as research targets have been proposed, their explanatory powers have not yet been compared. Our...
Reese Richardson

The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease

22 hours 46 minutes ago
We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer's disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in...
Jordi Manuello

Phosphorylation and O-GlcNAcylation at the same α-synuclein site generate distinct fibril structures

22 hours 46 minutes ago
α-Synuclein forms amyloid fibrils that are critical in the progression of Parkinson's disease and serves as the pathological hallmark of this condition. Different posttranslational modifications have been identified at multiple sites of α-synuclein, influencing its conformation, aggregation and function. Here, we investigate how disease-related phosphorylation and O-GlcNAcylation at the same α-synuclein site (S87) affect fibril structure and neuropathology. Using semi-synthesis, we obtained...
Jinjian Hu

Single-cell multiplex chromatin and RNA interactions in ageing human brain

22 hours 46 minutes ago
Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA^(1-3). Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells^(4-7). Here we introduce the multinucleic acid interaction mapping in single cells (MUSIC) technique for concurrent profiling of multiplex chromatin interactions, gene expression and...
Xingzhao Wen

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models

22 hours 46 minutes ago
Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated...
Edward N Wilson

Xenografted human microglia display diverse transcriptomic states in response to Alzheimer's disease-related amyloid-beta pathology

22 hours 46 minutes ago
Microglia are central players in Alzheimer's disease pathology but analyzing microglial states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the App^(NL-G-F) model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar...
Renzo Mancuso

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles

22 hours 46 minutes ago
The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and...
Chris G Faulkes

The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease

22 hours 46 minutes ago
We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer's disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in...
Jordi Manuello

Formation of memory assemblies through the DNA-sensing TLR9 pathway

22 hours 46 minutes ago
As hippocampal neurons respond to diverse types of information¹, a subset assembles into microcircuits representing a memory². Those neurons typically undergo energy-intensive molecular adaptations, occasionally resulting in transient DNA damage^(3-5). Here we found discrete clusters of excitatory hippocampal CA1 neurons with persistent double-stranded DNA (dsDNA) breaks, nuclear envelope ruptures and perinuclear release of histone and dsDNA fragments hours after learning. Following these early...
Vladimir Jovasevic

Single-cell multiplex chromatin and RNA interactions in ageing human brain

22 hours 46 minutes ago
Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA^(1-3). Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells^(4-7). Here we introduce the multinucleic acid interaction mapping in single cells (MUSIC) technique for concurrent profiling of multiplex chromatin interactions, gene expression and...
Xingzhao Wen

Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity

22 hours 46 minutes ago
Ageing of the immune system is characterized by decreased lymphopoiesis and adaptive immunity, and increased inflammation and myeloid pathologies^(1,2). Age-related changes in populations of self-renewing haematopoietic stem cells (HSCs) are thought to underlie these phenomena³. During youth, HSCs with balanced output of lymphoid and myeloid cells (bal-HSCs) predominate over HSCs with myeloid-biased output (my-HSCs), thereby promoting the lymphopoiesis required for initiating adaptive immune...
Jason B Ross