The Interaction Effects of Sex, Age, APOE and Common Health Risk Factors on Human Brain Functions.

Importance: Nonlinear changes in brain function during aging are shaped by a complex interplay of factors, including sex, age, genetics, and modifiable health risk factors. However, the combined effects and underlying mechanisms of these factors on brain functional connectivity remain poorly understood.

Objective: To comprehensively investigate the combined associations of sex, age, genotypes, and ten common modifiable health risk factors with brain functional connectivities during aging.

Advancements in high-resolution 3D microscopy analysis of endosomal morphology in postmortem Alzheimer's disease brains.

Abnormal endo-lysosomal morphology is an early cytopathological feature of Alzheimer's disease (AD) and genome-wide association studies (GWAS) have implicated genes involved in the endo-lysosomal network (ELN) as conferring increased risk for developing sporadic, late-onset AD (LOAD). Characterization of ELN pathology and the underlying pathophysiology is a promising area of translational AD research and drug development. However, rigorous study of ELN vesicles in AD and aged control brains poses a unique constellation of methodological challenges due in part to the small size of these structures and subsequent requirements for high-resolution imaging.

The interaction effects of age, APOE and common environmental risk factors on human brain structure.

Mounting evidence suggests considerable diversity in brain aging trajectories, primarily arising from the complex interplay between age, genetic, and environmental risk factors, leading to distinct patterns of micro- and macro-cerebral aging. The underlying mechanisms of such effects still remain unclear. We conducted a comprehensive association analysis between cerebral structural measures and prevalent risk factors, using data from 36,969 UK Biobank subjects aged 44-81.

Human microglia show unique transcriptional changes in Alzheimer's disease.

Microglia, the innate immune cells of the brain, influence Alzheimer's disease (AD) progression and are potential therapeutic targets. However, microglia exhibit diverse functions, the regulation of which is not fully understood, complicating therapeutics development. To better define the transcriptomic phenotypes and gene regulatory networks associated with AD, we enriched for microglia nuclei from 12 AD and 10 control human dorsolateral prefrontal cortices (7 males and 15 females, all aged >60 years) before single-nucleus RNA sequencing.

Microglia specific deletion of miR-155 in Alzheimer's disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures.

Alzheimer's Disease (AD) is characterized by the accumulation of extracellular amyloid-β (Aβ) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer's disease (AD) patients.

The Neuroscience Multi-Omic Archive: a BRAIN Initiative resource for single-cell transcriptomic and epigenomic data from the mammalian brain.

Scalable technologies to sequence the transcriptomes and epigenomes of single cells are transforming our understanding of cell types and cell states. The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative Cell Census Network (BICCN) is applying these technologies at unprecedented scale to map the cell types in the mammalian brain. In an effort to increase data FAIRness (Findable, Accessible, Interoperable, Reusable), the NIH has established repositories to make data generated by the BICCN and related BRAIN Initiative projects accessible to the broader research community.

A cAMP-Related Gene Network in Microglia Is Inversely Regulated by Morphine Tolerance and Withdrawal.

Background: Microglia have recently been implicated in opioid dependence and withdrawal. Mu Opioid (MOR) receptors are expressed in microglia, and microglia form intimate connections with nearby neurons. Accordingly, opioids have both direct (MOR mediated) and indirect (neuron-interaction mediated) effects on microglia function.

Validation of a computational phenotype for finding patients eligible for genetic testing for pathogenic PTEN variants across three centers.

Background: Computational phenotypes are most often combinations of patient billing codes that are highly predictive of disease using electronic health records (EHR). In the case of rare diseases that can only be diagnosed by genetic testing, computational phenotypes identify patient cohorts for genetic testing and possible diagnosis. This article details the validation of a computational phenotype for PTEN hamartoma tumor syndrome (PHTS) against the EHR of patients at three collaborating clinical research centers: Boston Children's Hospital, Children's National Hospital, and the University of Washington.

Brain capillary obstruction during neurotoxicity in a mouse model of anti-CD19 chimeric antigen receptor T-cell therapy.

Immunotherapy for haematologic malignancies with CD19-directed chimeric antigen receptor T cells has been highly successful at eradicating cancer but is associated with acute neurotoxicity in ∼40% of patients. This neurotoxicity correlates with systemic cytokine release syndrome, endothelial activation and disruption of endothelial integrity, but it remains unclear how these mechanisms interact and how they lead to neurologic dysfunction. We hypothesized that dysfunction of the neurovascular unit is a key step in the development of neurotoxicity.

A Subpopulation of Microglia Generated in the Adult Mouse Brain Originates from Prominin-1-Expressing Progenitors.

Microglia maintain brain health and play important roles in disease and injury. Despite the known ability of microglia to proliferate, the precise nature of the population or populations capable of generating new microglia in the adult brain remains controversial. We identified Prominin-1 (Prom1; also known as CD133) as a putative cell surface marker of committed brain myeloid progenitor cells.

The pro-inflammatory microRNA miR-155 influences fibrillar β-Amyloid catabolism by microglia.

Microglia are the innate immune cells of the central nervous system that adopt rapid functional changes in response to Damage Associated Molecular Patterns, including aggregated β-Amyloid (Aβ) found in Alzheimer's disease (AD). microRNAs (miRNAs) are post-transcriptional modulators that influence the timing and magnitude of microglia inflammatory responses by downregulating the expression of inflammatory effectors. Recent studies implicate miR-155, a miRNA known to regulate inflammatory responses, in the pathogenesis of neurodegenerative disorders including multiple sclerosis, ALS, familial Parkinson's disease, and AD.

Cytokines in CAR T Cell-Associated Neurotoxicity.

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema.

Author Correction: Molecular estimation of neurodegeneration pseudotime in older brains.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-20261-6.

Molecular estimation of neurodegeneration pseudotime in older brains.

The temporal molecular changes that lead to disease onset and progression in Alzheimer's disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage-or disease pseudotime-for each sample.

Early-Onset Familial Alzheimer Disease Variant PSEN2 N141I Heterozygosity is Associated with Altered Microglia Phenotype.

Background: Early-onset familial Alzheimer disease (EOFAD) is caused by heterozygous variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), and APP genes. Decades after their discovery, the mechanisms by which these genes cause Alzheimer's disease (AD) or promote AD progression are not fully understood. While it is established that presenilin (PS) enzymatic activity produces amyloid-β (Aβ), PSs also regulate numerous other cellular functions, some of which intersect with known pathogenic drivers of neurodegeneration.

Ischemic preconditioning induces cortical microglial proliferation and a transcriptomic program of robust cell cycle activation.

Ischemic preconditioning (IPC) is an experimental phenomenon in which a subthreshold ischemic insult applied to the brain reduces damage caused by a subsequent more severe ischemic episode. Identifying key molecular and cellular mediators of IPC will provide critical information needed to develop novel therapies for stroke. Here we report that the transcriptomic response of acutely isolated preconditioned cortical microglia is dominated by marked upregulation of genes involved in cell cycle activation and cellular proliferation.

Alternative splicing in a presenilin 2 variant associated with Alzheimer disease.

Objective: Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (), presenilin 2 (), and amyloid precursor protein (). Previously, we reported a rare frameshift variant in an early-onset AD case (PSEN2 p.K115Efs*11).

Modulation of Hematopoietic Lineage Specification Impacts TREM2 Expression in Microglia-Like Cells Derived From Human Stem Cells.

Microglia are the primary innate immune cell type in the brain, and their dysfunction has been linked to a variety of central nervous system disorders. Human microglia are extraordinarily difficult to obtain for experimental investigation, limiting our ability to study the impact of human genetic variants on microglia functions. Previous studies have reported that microglia-like cells can be derived from human monocytes or pluripotent stem cells.

Glial biomarkers in human central nervous system disease.

There is a growing understanding that aberrant GLIA function is an underlying factor in psychiatric and neurological disorders. As drug discovery efforts begin to focus on glia-related targets, a key gap in knowledge includes the availability of validated biomarkers to help determine which patients suffer from dysfunction of glial cells or who may best respond by targeting glia-related drug mechanisms. Biomarkers are biological variables with a significant relationship to parameters of disease states and can be used as surrogate markers of disease pathology, progression, and/or responses to drug treatment.

The p53 Transcriptional Network Influences Microglia Behavior and Neuroinflammation.

The tumor-suppressor protein p53 belongs to a family of proteins that play pivotal roles in multiple cellular functions including cell proliferation, cell death, genome stability, and regulation of inflammation. Neuroinflammation is a common feature of central nervous system (CNS) pathology, and microglia are the specialized resident population of CNS myeloid cells that initiate innate immune responses. Microglia maintain CNS homeostasis through pathogen containment, phagocytosis of debris, and initiation of tissue-repair cascades.

MicroRNAs mediating CNS inflammation: Small regulators with powerful potential.

MicroRNAs (miRNAs) are a family of small non-coding RNAs (~22 nucleotides) that fine-tune protein expression by either silencing mRNA translation or directly targeting gene transcripts for degradation. In the central nervous system (CNS), neuroinflammation plays a critical role in brain injury and neurodegeneration. Increasing evidence supports the involvement of miRNAs as key regulators of neuroinflammation.

R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study.

Importance: The R47H variant in the triggering receptor expressed on myeloid cells 2 gene (TREM2), a modulator of the immune response of microglia, is a strong genetic risk factor for Alzheimer disease (AD) and possibly other neurodegenerative disorders.

Objective: To investigate a large family with late-onset AD (LOAD), in which R47H cosegregated with 75% of cases.

Design, Setting, And Participants: This study includes genetic and pathologic studies of families with LOAD from 1985 to 2014.