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Myelin-axon interface vulnerability in Alzheimer's disease revealed by subcellular proteomics and imaging of human and mouse brain

2 weeks 3 days ago
Myelin ensheathment is essential for rapid axonal conduction, metabolic support and neuronal plasticity. In Alzheimer's disease (AD), disruptions in myelin and axonal structures occur, although the underlying mechanisms remain unclear. We implemented proximity labeling subcellular proteomics of the myelin-axon interface in postmortem human brains from AD donors and 15-month-old male and female 5XFAD mice. We uncovered multiple dysregulated signaling pathways and ligand-receptor interactions,...
Yifei Cai

Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength

2 weeks 3 days ago
Repair of muscle damage declines with age due to the accumulation of dysfunctional muscle stem cells (MuSCs). Here, we uncover that aged MuSCs have blunted prostaglandin E2 (PGE2)-EP4 receptor signaling, which causes precocious commitment and mitotic catastrophe. Treatment with PGE2 alters chromatin accessibility and overcomes the dysfunctional aged MuSC fate trajectory, increasing viability and triggering cell cycle re-entry. We employ neural network models to learn the complex logic of...
Yu Xin Wang

SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging

2 weeks 3 days ago
Sirtuin enzymes are deeply associated with senescence and aging. Sirtuin proteins are tightly regulated, but how their levels are governed during aging and how they elicit tissue-specific cellular changes are unclear. Here, we demonstrate that SIRT7 undergoes proteasomal degradation during senescence via targeting by the E3 ligase TRIP12. We identified the transcription factor nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) as an interactor of SIRT7 and found NUCKS1...
Khoa A Tran

Senescence in cancer

2 weeks 3 days ago
Cellular senescence is a state of stable cell-cycle arrest induced by various intrinsic and extrinsic stressors, serving as a protective mechanism to prevent the proliferation of damaged cells. While this process is crucial for tissue homeostasis and tumor suppression, the progressive accumulation of senescent cells (SnCs) over time is implicated in age-related pathologies, including immune dysfunction and cancer. In oncology, senescence plays a paradoxical role: it can inhibit tumor development...
Manuel Colucci

Exercise alters transcriptional profiles of senescence and gut barrier integrity in intestinal crypts of aging mice

2 weeks 3 days ago
Senescence is the gradual process of aging in tissues and cells, and a primary cause of aging-associated diseases. Among them, intestinal stem cells (ISCs) experience exhaustion during aging, leading to reduced regenerative capacity in the intestinal crypt, which impairs intestinal function and contributes to systemic health issues. Given the critical role ISCs play in maintaining intestinal homeostasis, preventing their senescence is essential for preserving intestinal function. Among the...
Hyeonuk Jeon

The amyloid precursor family of proteins in excitatory neurons are essential for regulating cortico-hippocampal circuit dynamics in vivo

2 weeks 3 days ago
The amyloid precursor protein (APP) family is ubiquitously expressed in the mammalian brain and implicated in Alzheimer's disease. APP family proteins participate in synaptic function and their absence impairs cognition. However, how these proteins regulate neural circuits and influence brain-behavior relationships remains unknown. Using in vivo two-photon Ca^(2+)-imaging and Neuropixels, we show that APP family knockout (KO) in excitatory neocortical and hippocampal neurons suppresses neuronal...
Samuel S Harris

Top-down attention and Alzheimer's pathology affect cortical selectivity during learning, influencing episodic memory in older adults

2 weeks 3 days ago
Effective memory formation declines in human aging. Diminished neural selectivity-reduced differential responses to preferred versus nonpreferred stimuli-may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During...
Jintao Sheng

Transgenerational epigenetic effect of kings' aging on offspring's caste fate mediated by sperm DNA methylation in termites

2 weeks 3 days ago
The discovery of transgenerational epigenetic inheritance and the unraveling of its molecular mechanisms are currently solving previously puzzling challenges that Mendelian genetics based solely on DNA could not explain, leading to significant paradigm shifts across various fields of biology. There has been a long-standing controversy over the factors determining the caste fate of individuals in social insects. Increasing evidence supports heritable influences on division of labor. Here, we...
Mamoru Takata

Cerebral Metabolic Rate of Oxygen and Accelerometry-Based Fatigability in Community-Dwelling Older Adults

2 weeks 3 days ago
Alterations in energy metabolism may drive fatigue in older age, but prior research primarily focused on skeletal muscle energetics without assessing other systems and utilized self-reported measures of fatigue. We tested the association between energy metabolism in the brain and an objective measure of fatigability in the Study of Muscle, Mobility and Aging (N = 119, age 76.8 ± 4.0 years, 59.7% women). Total brain cerebral metabolic rate of oxygen (CMRO(2)) was measured using arterial spin...
Emma L Gay

Top-down attention and Alzheimer's pathology affect cortical selectivity during learning, influencing episodic memory in older adults

2 weeks 3 days ago
Effective memory formation declines in human aging. Diminished neural selectivity-reduced differential responses to preferred versus nonpreferred stimuli-may contribute to memory decline, but its drivers remain unclear. We investigated the effects of top-down attention and preclinical Alzheimer's disease (AD) pathology on neural selectivity in 166 cognitively unimpaired older participants using functional magnetic resonance imaging during a word-face/word-place associative memory task. During...
Jintao Sheng