Paranodal instability driven by axonal mitochondrial accumulation in ischemic demyelination and cognitive decline
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Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease
Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer’s disease (AD), where they impair axonal electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover the proteome of spheroids in human postmortem and mouse brains. Additionally, we established a human induced pluripotent stem cell (iPSC)-derived AD model enabling mechanistic investigation and optical electrophysiology. These complementary approaches revealed the subcellular molecular architecture of spheroids and identified abnormalities in key biological processes, including protein turnover, cytoskeleton dynamics and lipid transport. Notably, the PI3K/AKT/mTOR pathway, which regulates these processes, was activated in spheroids. Furthermore, phosphorylated mTOR levels in spheroids correlated with AD severity in humans. Notably, mTOR inhibition in iPSC-derived neurons and mice ameliorated spheroid pathology. Altogether, our study provides a multidisciplinary toolkit for investigating mechanisms and therapeutic targets for axonal pathology in neurodegeneration.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
Smartwatch- and smartphone-based remote assessment of brain health and detection of mild cognitive impairment
Consumer-grade mobile devices are used by billions worldwide. Their ubiquity provides opportunities to robustly capture everyday cognition. ‘Intuition’ was a remote observational study that enrolled 23,004 US adults, collecting 24 months of longitudinal multimodal data via their iPhones and Apple Watches using a custom research application that captured routine device use, self-reported health information and cognitive assessments. The study objectives were to classify mild cognitive impairment (MCI), characterize cognitive trajectories and develop tools to detect and track cognitive health at scale. The study addresses sources of bias in current cognitive health research, including limited representativeness (for example, racial/ethnic, geographic) and accuracy of cognitive measurement tools. We describe study design and provide baseline cohort characteristics. Next, we present foundational proof-of-concept MCI classification modeling results using interactive cognitive assessment data. Initial findings support the reliability and validity of remote MCI detection and the usefulness of such data in describing at-risk cognitive health trajectories in demographically diverse aging populations. ClinicalTrials.gov identifier: NCT05058950.
Boredom signals deviation from a cognitive homeostatic set point
Boredom is the feeling of wanting but failing to engage the mind and can be conceived as one among many signals of suboptimal utilization of cognitive and neural resources. Using homeostasis as an analogy, this perspective argues that boredom represents a signal indicating deviation from optimal engagement—that is, deviation from a cognitive homeostatic set point. Within this model, allostasis accounts for chronic boredom (i.e., trait boredom proneness), according to which faulty internal models are responsible for why the highly boredom prone may set unrealistic expectations for engagement. In other words, the model characterizes boredom as a dynamic response to both internal and external exigencies, leading to testable hypotheses for both the nature of the state and the trait disposition. Furthermore, this perspective presents the broader notion that humans strive to optimally engage with their environs to maintain a kind of cognitive homeostatic set-point.
Cognitive reserve is associated with education, social determinants, and cognitive outcomes among older American Indians in the Strong Heart Study
Cognitive reserve, a component of resilience, may be conceptualized as the ability to overcome accumulating neuropathology and maintain healthy aging and function. However, research measuring and evaluating it in American Indians is needed. We recruited American Indians from 3 regional centers for longitudinal examinations (2010-13, n = 818; 2017-19, n = 403) including MRI, cognitive, clinical, and questionnaire data. We defined cognitive reserve by measuring the residual from individual regressions of cognitive tests over imaged brain volumes, adjusted for age and sex. Analyses examined three different metrics of cognitive reserve against sociodemographic, clinical, and longitudinal cognitive data in causal mediation models. Better cognitive reserve was significantly associated with more education, higher income, lower prevalence of depression, lower prevalence of diabetes, and lower prevalence of kidney disease, but we found no statistically significant evidence for an association with plasma biomarkers for Alzheimer’s disease and related dementias, APOE e4 carrier status, alcohol use, body mass, or hypertension. Better cognitive reserve was associated with better cognitive function over mean 6.7 years follow-up (range 4-9 years); and the association for education with cognition over time was mediated in part (15-24%) by cognitive reserve. Cognitive reserve, although challenging to measure, appears important for understanding the range of cognitive aging in American Indians.
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