Single-cell analysis of innate spinal cord regeneration identifies intersecting modes of neuronal repair.

Adult zebrafish have an innate ability to recover from severe spinal cord injury. Here, we report a comprehensive single nuclear RNA sequencing atlas that spans 6 weeks of regeneration. We identify cooperative roles for adult neurogenesis and neuronal plasticity during spinal cord repair.

Modeling late-onset Alzheimer's disease neuropathology via direct neuronal reprogramming.

Late-onset Alzheimer's disease (LOAD) is the most common form of Alzheimer's disease (AD). However, modeling sporadic LOAD that endogenously captures hallmark neuronal pathologies such as amyloid-β (Aβ) deposition, tau tangles, and neuronal loss remains an unmet need. We demonstrate that neurons generated by microRNA (miRNA)-based direct reprogramming of fibroblasts from individuals affected by autosomal dominant AD (ADAD) and LOAD in a three-dimensional environment effectively recapitulate key neuropathological features of AD.

Mistargeted retinal axons induce a synaptically independent subcircuit in the visual thalamus of albino mice.

In albino mice and EphB1 knock out mice, mistargeted retinal ganglion cell (RGC) axons form dense islands of axon terminals in the dorsal lateral geniculate nuclei (dLGN). The formation of these islands of retinal input depends on developmental patterns of spontaneous retinal activity. We reconstructed the microcircuitry of the activity dependent islands and found that the boundaries of the island represent a remarkably strong segregation within retinogeniculate connectivity.

Insufficient evidence for an association between iatrogenic Alzheimer's disease and cadaveric pituitary-derived growth hormone.

A Nature Medicine paper published in January 2024 describes eight cases of iatrogenic Alzheimer's disease in individuals who received cadaveric pituitary-derived human growth hormone. The paper's conclusions argue for the transmissibility of Alzheimer's disease, which, if true, would create a significant public health crisis. For example, neurosurgical practices would require substantial revision, and many individuals who have undergone neurosurgical procedures would now be at considerable risk of Alzheimer's disease.

Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference.

Introduction: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research.

A Comprehensive Head-to-Head Comparison of Key Plasma Phosphorylated Tau 217 Biomarker Tests.

Plasma phosphorylated-tau 217 (p-tau217) is currently the most promising biomarkers for reliable detection of Alzheimer's disease (AD) pathology. Various p-tau217 assays have been developed, but their relative performance is unclear. We compared key plasma p-tau217 tests using cross-sectional and longitudinal measures of amyloid-β (Aβ)-PET, tau-PET, and cognition as outcomes, and benchmarked them against cerebrospinal fluid (CSF) biomarker tests.

An emerging role for the gut microbiome in tauopathy.

Tauopathies constitute a group of neurodegenerative diseases characterized by abnormal aggregation of the protein tau, progressive neuronal and synaptic loss, and eventual cognitive and motor impairment. In this review, we will highlight the latest efforts investigating the intricate interplay between the gut microbiome and tauopathies. We discuss the physiological interactions between the microbiome and the brain as well as clinical and experimental evidence that suggests that the presence of tauopathy alters the composition of gut microbiota.

Apolipoprotein E in Alzheimer's disease trajectories and the next-generation clinical care pathway.

Alzheimer's disease (AD) is a complex, progressive primary neurodegenerative disease. Since pivotal genetic studies in 1993, the ε4 allele of the apolipoprotein E gene (APOE ε4) has remained the strongest single genome-wide associated risk variant in AD. Scientific advances in APOE biology, AD pathophysiology and ApoE-targeted therapies have brought APOE to the forefront of research, with potential translation into routine AD clinical care.

Cis-regulatory evolution of the recently expanded Ly49 gene family.

Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However, less is known about the evolution of their epigenome and cis-regulation.

Seq-ing mechanisms behind types of Alzheimer's disease.

Sporadic Alzheimer's disease (AD) and autosomal dominant Alzheimer's disease (ADAD) share pathological features, but differing mechanisms, leading to disease. In this issue of Neuron, Almeida, Eger, et al. uncovered molecular processes that may distinguish sporadic AD from ADAD and how the APOE-Christchurch variant may be protective.

Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer's disease.

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens.

An inducible genetic tool to track and manipulate specific microglial states reveals their plasticity and roles in remyelination.

Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia (PAMs) in developing white matter and disease-associated microglia (DAMs) prevalent in various neurodegenerative conditions. PAMs and DAMs share a similar core gene signature.

Post-GWAS multiomic functional investigation of the TNIP1 locus in Alzheimer's disease highlights a potential role for GPX3.

Introduction: Recent genome-wide association studies (GWAS) have reported a genetic association with Alzheimer's disease (AD) at the TNIP1/GPX3 locus, but the mechanism is unclear.

Methods: We used cerebrospinal fluid (CSF) proteomics data to test (n = 137) and replicate (n = 446) the association of glutathione peroxidase 3 (GPX3) with CSF biomarkers (including amyloid and tau) and the GWAS-implicated variants (rs34294852 and rs871269).

Results: CSF GPX3 levels decreased with amyloid and tau positivity (analysis of variance P = 1.

mosGraphGen: a novel tool to generate multi-omics signaling graphs to facilitate integrative and interpretable graph AI model development.

Multi-omics data, i.e., genomics, epigenomics, transcriptomics, proteomics, characterize cellular complex signaling systems from multi-level and multi-view and provide a holistic view of complex cellular signaling pathways.

A role of dentate gyrus mechanistic target of rapamycin activation in epileptogenesis in a mouse model of posttraumatic epilepsy.

Objective: The mechanistic target of rapamycin (mTOR) pathway has been implicated in promoting epileptogenesis in animal models of acquired epilepsy, such as posttraumatic epilepsy (PTE) following traumatic brain injury (TBI). However, the specific anatomical regions and neuronal populations mediating mTOR's role in epileptogenesis are not well defined. In this study, we tested the hypothesis that mTOR activation in dentate gyrus granule cells promotes neuronal death, mossy fiber sprouting, and PTE in the controlled cortical impact (CCI) model of TBI.

Midpoint of sleep is associated with sleep quality in older adults with and without symptomatic Alzheimer's disease.

Introduction: Disrupted sleep is common in individuals with Alzheimer's disease (AD) and may be a marker for AD risk. The timing of sleep affects sleep-wake activity and is also associated with AD, but little is known about links between sleep architecture and the midpoint of sleep in older adults. In this study, we tested if the midpoint of sleep is associated with different measures of sleep architecture, AD biomarkers, and cognitive status among older adults with and without symptomatic AD.

Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer's disease.

Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles.

Inhibitory Roles of Christchurch Astrocytes in Curbing Tau Propagation Using Human Pluripotent Stem Cell-Derived Models.

Genetic variants in the () gene affect the onset and progression of Alzheimer's disease (AD). The Christchurch ( Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic Ch/Ch human-induced pluripotent stem cells (iPSCs) from / healthy control female iPSCs and induced them into astrocytes.

CSF biomarkers of immune activation and Alzheimer's disease for predicting cognitive impairment risk in the elderly.

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 ( = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels.