Microglia depletion reduces human neuronal APOE4-related pathologies in a chimeric Alzheimer's disease model.

Despite strong evidence supporting the important roles of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-related AD pathogenesis remain elusive. To examine such effects, we utilized microglial depletion in a chimeric model with induced pluripotent stem cell (iPSC)-derived human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) iPSC-derived human neurons into the hippocampus of human APOE3 or APOE4 knockin mice and then depleted microglia in half of the chimeric mice.

Facing the unthinkable: Life-threatening illness in the analyst and its impact on the analytic couple.

This article explores the impact of the analyst's life-threatening illness on the analytic couple; it is informed through two theoretical lenses - Freud's ideas about the vicissitudes of mourning, which have been elaborated on by Melanie Klein and John Steiner, and Christopher Bollas's ideas about destiny and idiom. Clinical material will focus on my on-going work with a middle-aged man who has a history of early abandonment and loss and who struggles with being able to remain separate from his objects while being in relationship with them.

Microglia Depletion Reduces Human Neuronal APOE4-Driven Pathologies in a Chimeric Alzheimer's Disease Model.

Despite strong evidence supporting the involvement of both apolipoprotein E4 (APOE4) and microglia in Alzheimer's Disease (AD) pathogenesis, the effects of microglia on neuronal APOE4-driven AD pathogenesis remain elusive. Here, we examined such effects utilizing microglial depletion in a chimeric model with human neurons in mouse hippocampus. Specifically, we transplanted homozygous APOE4, isogenic APOE3, and APOE-knockout (APOE-KO) induced pluripotent stem cell (iPSC)-derived human neurons into the hippocampus of human APOE3 or APOE4 knock-in mice, and depleted microglia in half the chimeric mice.

The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier.

APOE4-promoted gliosis and degeneration in tauopathy are ameliorated by pharmacological inhibition of HMGB1 release.

Apolipoprotein E4 (APOE4) is an important driver of Tau pathology, gliosis, and degeneration in Alzheimer's disease (AD). Still, the mechanisms underlying these APOE4-driven pathological effects remain elusive. Here, we report in a tauopathy mouse model that APOE4 promoted the nucleocytoplasmic translocation and release of high-mobility group box 1 (HMGB1) from hippocampal neurons, which correlated with the severity of hippocampal microgliosis and degeneration.

Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits.

Apolipoprotein E4 (APOE4) is the strongest known genetic risk factor for late-onset Alzheimer's disease (AD). Conditions of stress or injury induce APOE expression within neurons, but the role of neuronal APOE4 in AD pathogenesis is still unclear. Here we report the characterization of neuronal APOE4 effects on AD-related pathologies in an APOE4-expressing tauopathy mouse model.

Dentate gyrus and CA3 GABAergic interneurons bidirectionally modulate signatures of internal and external drive to CA1.

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV) and somatostatin-expressing (SST), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood.

Apolipoprotein E and Alzheimer's Disease: Findings, Hypotheses, and Potential Mechanisms.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves dysregulation of many cellular and molecular processes. It is notoriously difficult to develop therapeutics for AD due to its complex nature. Nevertheless, recent advancements in imaging technology and the development of innovative experimental techniques have allowed researchers to perform in-depth analyses to uncover the pathogenic mechanisms of AD.

Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer's disease.

Selective neurodegeneration is a critical causal factor in Alzheimer's disease (AD); however, the mechanisms that lead some neurons to perish, whereas others remain resilient, are unknown. We sought potential drivers of this selective vulnerability using single-nucleus RNA sequencing and discovered that ApoE expression level is a substantial driver of neuronal variability. Strikingly, neuronal expression of ApoE-which has a robust genetic linkage to AD-correlated strongly, on a cell-by-cell basis, with immune response pathways in neurons in the brains of wild-type mice, human ApoE knock-in mice and humans with or without AD.

Alzheimer's Gone Viral: Could Herpes Simplex Virus Type-1 Be Stealing Your Memories?

Alzheimer's disease (AD) is one of the principal causes of disability and morbidity. It is one of the most expensive illnesses. Despite this, there are no significant data regarding its etiology and optimal treatment.

Survival of the Fittest: Addressing the Disparities in the Burden of Chronic Kidney Disease.

The prevalence of chronic kidney disease (CKD) is increasingly becoming recognized as a global health concern as well as a critical determinant of poor health outcomes. Decreased access to health care and low socioeconomic status (SES) worsen the adverse effects of biologic or genetic predisposition to CKD. All the studies used were retrieved using the PubMed database.

Cannabis, More Than the Euphoria: Its Therapeutic Use in Drug-Resistant Epilepsy.

A significant number of epilepsy patients are refractory to conventional antiepileptic drugs. These patients experience considerable neurocognitive impairments that impact their quality of life and ability to function independently. This need for alternative treatment has generated increased interest in cannabis use as a therapeutic option in these patients.

In Vivo Chimeric Alzheimer's Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons.

Despite its clear impact on Alzheimer's disease (AD) risk, apolipoprotein (apo) E4's contributions to AD etiology remain poorly understood. Progress in answering this and other questions in AD research has been limited by an inability to model human-specific phenotypes in an in vivo environment. Here we transplant human induced pluripotent stem cell (hiPSC)-derived neurons carrying normal apoE3 or pathogenic apoE4 into human apoE3 or apoE4 knockin mouse hippocampi, enabling us to disentangle the effects of apoE4 produced in human neurons and in the brain environment.

A Mother's Cry: A Race to Eliminate the Influence of Racial Disparities on Maternal Morbidity and Mortality Rates Among Black Women in America.

Racial/ethnic disparities in maternal care exist, even as medicine continues to progress on several aspects, medical care continues to fail countless women each year, particularly minority women and women of color. Black and American Indian/Alaska Native women experienced exponentially more pregnancy-related deaths. Recognizing factors that underlie disparities in pregnancy-related deaths and implementing preventive approaches to resolve them may mitigate racial/ethnic disparities in pregnancy-related mortality.

Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation.

Intercellular propagation of protein aggregation is emerging as a key mechanism in the progression of several neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia (FTD). However, we lack a systematic understanding of the cellular pathways controlling prion-like propagation of aggregation. To uncover such pathways, here we performed CRISPR interference (CRISPRi) screens in a human cell-based model of propagation of tau aggregation monitored by FRET.

Correction to: Burden of caregivers of adult patients with schizophrenia in a predominantly African ancestry population.

In the original publication, the co-author name Kelly-Marie Chen was misspelled and Shenae Miller was missed in the author group. The correct author group has been provided in this correction.

A high-throughput screen of real-time ATP levels in individual cells reveals mechanisms of energy failure.

Insufficient or dysregulated energy metabolism may underlie diverse inherited and degenerative diseases, cancer, and even aging itself. ATP is the central energy carrier in cells, but critical pathways for regulating ATP levels are not systematically understood. We combined a pooled clustered regularly interspaced short palindromic repeats interference (CRISPRi) library enriched for mitochondrial genes, a fluorescent biosensor, and fluorescence-activated cell sorting (FACS) in a high-throughput genetic screen to assay ATP concentrations in live human cells.

Burden of caregivers of adult patients with schizophrenia in a predominantly African ancestry population.

Purpose: There is relative inattention to caregiving burden in black populations in developing economies. This study seeks to assess the level of perceived burden and social determinants of burden of care in caregivers of adult patients with schizophrenia.

Methods: In this cross-sectional study, 115 dyads of patients with schizophrenia caregivers attending public mental health clinics were consecutively recruited.