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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. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD. Nelson et al. report that the APOE-R136S mutation protects against APOE4-promoted Alzheimer’s disease pathologies, including phosphorylated Tau accumulation, neuroinflammation and neurodegeneration, in mouse and human neuron models.

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. Elimination or over-expression of neuronal ApoE revealed a causal relationship among ApoE expression, neuronal MHC-I expression, tau pathology and neurodegeneration. Functional reduction of MHC-I ameliorated tau pathology in ApoE4-expressing primary neurons and in mouse hippocampi expressing pathological tau. These findings suggest a mechanism linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration. Selective neurodegeneration is a critical causal factor in Alzheimer’s disease. Zalocusky et al. demonstrate a causal chain linking neuronal ApoE expression to MHC-I expression and, subsequently, to tau pathology and selective neurodegeneration.

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. The selective genetic removal of APOE4 from neurons led to a significant reduction in tau pathology, gliosis, neurodegeneration, neuronal hyperexcitability and myelin deficits. Single-nucleus RNA-sequencing revealed that the removal of neuronal APOE4 greatly diminished neurodegenerative disease-associated subpopulations of neurons, oligodendrocytes, astrocytes and microglia whose accumulation correlated to the severity of tau pathology, neurodegeneration and myelin deficits. Thus, neuronal APOE4 plays a central role in promoting the development of major AD pathologies and its removal can mitigate the progressive cellular and tissue alterations occurring in this model of APOE4-driven tauopathy.

Homozygous APOE3-Christchurch (R136S) mutation protects a presenilin 1 ( PSEN1) mutation carrier from developing Alzheimer’s disease until her seventies.

The greatest genetic risk factor for late-onset Alzheimer's disease (AD) is Apolipoprotein E (APOE)*ε4. Preclinical studies have demonstrated that genetic ablation or reduction of APOE4 mRNA in amyloid and tauopathy mouse models have protective effects and/or reduce pathology. Targeting central APOE, while sparing systemic APOE and cholesterol metabolism, is the holy grail for a precision medicine approach in APOE*ε4 carriers with MCI/AD. Here, we present data for the first time, demonstrating our novel, highly potent, conditionally activating siRNA (CASi) targeting APOE mRNA in the brain while sparing peripheral APOE. A library of CASi and parental siRNA molecules targeting APOE was designed and tested in iPSC astrocytes. The in vivo activity of the most potent compounds was evaluated in human APOE4 transgenic (hE4) mice over a dose concentration range. Activity was evaluated in both brain regions and the liver for lead selection. The lead molecule was further evaluated in nonhuman primate (NHP) studies, administered intrathecally at 112mg, 168mg, or 224mg doses. Knockdown of CSF, brain and liver tissue APOE was assessed at multiple time points. The potency of the lead CASi molecule was <20pM in iPSC astrocytes. A 10nmol dose yielded 60-85% reduction of APOE mRNA in hippocampal tissue at 2ng/mg CASi exposure. The molecule was well-tolerated in mice. No knockdown was observed in the liver, despite CASi exposure, and peripheral cholesterol levels were unchanged. The dose-response study demonstrated a tight PK/PD relationship with a significant (P<0.0001) negative correlation between CASi and APOE mRNA levels in hE4 mice. NHP studies demonstrated 50-75% APOE protein knockdown in the CSF 15 days post dosing, which was sustained until day 70. At 30 days post-dose, the entorhinal cortex and hippocampus showed a 50-75% knockdown. There was no reduction of APOE protein levels in liver or plasma across the study. We identified a potent CASi against APOE with no unwanted effects on liver APOE levels or peripheral cholesterol. The molecule holds promise as a future therapeutic for ε4 carriers suffering from MCI/AD, many of whom are contraindicated for the currently approved immunotherapies.

Background The greatest genetic risk factor for late‐onset Alzheimer’s disease (AD) is Apolipoprotein E (APOE)*ε4. Preclinical studies have demonstrated that genetic ablation or reduction of APOE4 mRNA in amyloid and tauopathy mouse models have protective effects and/or reduce pathology. Targeting central APOE, while sparing systemic APOE and cholesterol metabolism, is the holy grail for a precision medicine approach in APOE*ε4 carriers with MCI/AD. Here, we present data for the first time, demonstrating our novel, highly potent, conditionally activating siRNA (CASi) targeting APOE mRNA in the brain while sparing peripheral APOE. Method A library of CASi and parental siRNA molecules targeting APOE was designed and tested in iPSC astrocytes. The in vivo activity of the most potent compounds was evaluated in human APOE4 transgenic (hE4) mice over a dose concentration range. Activity was evaluated in both brain regions and the liver for lead selection. The lead molecule was further evaluated in nonhuman primate (NHP) studies, administered intrathecally at 112mg, 168mg, or 224mg doses. Knockdown of CSF, brain and liver tissue APOE was assessed at multiple time points. Result The potency of the lead CASi molecule was <20pM in iPSC astrocytes. A 10nmol dose yielded 60‐85% reduction of APOE mRNA in hippocampal tissue at 2ng/mg CASi exposure. The molecule was well‐tolerated in mice. No knockdown was observed in the liver, despite CASi exposure, and peripheral cholesterol levels were unchanged. The dose‐response study demonstrated a tight PK/PD relationship with a significant (P<0.0001) negative correlation between CASi and APOE mRNA levels in hE4 mice. NHP studies demonstrated 50‐75% APOE protein knockdown in the CSF 15 days post dosing, which was sustained until day 70. At 30 days post‐dose, the entorhinal cortex and hippocampus showed a 50‐75% knockdown. There was no reduction of APOE protein levels in liver or plasma across the study. Conclusion We identified a potent CASi against APOE with no unwanted effects on liver APOE levels or peripheral cholesterol. The molecule holds promise as a future therapeutic for ε4 carriers suffering from MCI/AD, many of whom are contraindicated for the currently approved immunotherapies.

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. We identified genes not known to be involved in energy metabolism. Most mitochondrial ribosomal proteins are essential in maintaining ATP levels under respiratory conditions, and impaired respiration predicts poor growth. We also identified genes for which coenzyme Q10 (CoQ10) supplementation rescued ATP deficits caused by knockdown. These included CoQ10 biosynthetic genes associated with human disease and a subset of genes not linked to CoQ10 biosynthesis, indicating that increasing CoQ10 can preserve ATP in specific genetic contexts. This screening paradigm reveals mechanisms of metabolic control and genetic defects responsive to energy-based therapies.

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. Future research on these disparities should focus on strategies for reducing racial/ethnic inequalities in pregnancy-related deaths, including improving access to high-quality preconception, maternity, and postpartum care for minority women, multi-ethnic education for physicians and healthcare providers in a bid to eliminate implicit biases, adequate funding, and improvement of healthcare facilities in minority areas, education of healthcare providers on variation in the incidence of some certain conditions in different ethnic groups so that care is patient-centered and culturally appropriate. All of these can be enforced through the community, healthcare facility, patient, family, physician, and system-level collaboration.

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. This review concentrates on the viral hypothesis of AD. After a comprehensive PubMed literature search, we analyzed the studies associating herpes simplex virus type-1 (HSV1) infection to AD from the previous 10 years. Molecular mechanisms whereby HSV1 induces AD-related pathophysiology, including neuronal production and accumulation of amyloid-beta (amyloid-β), abnormal phosphorylation of tau proteins, impaired calcium homeostasis, and autophagy, are addressed. The virus also imitates the disease in other ways, showing increased neuroinflammation, oxidative stress, synaptic dysfunction, and neuronal apoptosis. Serological studies correlate HSV1 infection with AD and cognitive impairment. A causal link between HSV1 and AD raises the concept of a simple, efficient, and preventive treatment alternative. Anti-viral agents impede brain degeneration by preventing HSV1 spread and its replication, decreasing hyperphosphorylated tau and amyloid-β; thus providing an efficacious treatment for AD. We also mention brown algae, intravenous immunoglobulin (IVIG), and a synthetic drug, BAY57-1293, with anti-viral properties, as options for treating AD. We want to recommend future researchers to look for more affordable, non-invasive, and swifter techniques to identify HSV1 in the brain and assist in the early detection and prevention of AD.

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. The literature suggests that in developing and developed countries, lower SES is inversely proportional to CKD. It shows an inconsistent relationship between CKD and race; that is, there may or may not be a relationship between these two variables. In the United States (US), the prevalence of the early stages of CKD is similar across different racial/ethnic groups. However, the preponderance of end-stage renal disease (ESRD) is higher for minorities than their non-Hispanic white counterparts. Further investigation is required to understand the role of racial disparities and CKD as well as to understand the significant difference seen in the incidence when progressing from CKD to ESRD. It is necessary to recognize how lower SES and racial/ethnic disparity may result in the impediment of appropriate disease management. A possible approach is the use of the biopsychosocial model, which integrates biological, individual, and neighborhood factors. A practical method of providing appropriate care to these populations will require economically feasible prevention strategies as well as extending the scope of dialysis by the implementation of cheaper alternatives.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. The literature suggests that in developing and developed countries, lower SES is inversely proportional to CKD. It shows an inconsistent relationship between CKD and race; that is, there may or may not be a relationship between these two variables. In the United States (US), the prevalence of the early stages of CKD is similar across different racial/ethnic groups. However, the preponderance of end-stage renal disease (ESRD) is higher for minorities than their non-Hispanic white counterparts. Further investigation is required to understand the role of racial disparities and CKD as well as to understand the significant difference seen in the incidence when progressing from CKD to ESRD. It is necessary to recognize how lower SES and racial/ethnic disparity may result in the impediment of appropriate disease management. A possible approach is the use of the biopsychosocial model, which integrates biological, individual, and neighborhood factors. A practical method of providing appropriate care to these populations will require economically feasible prevention strategies as well as extending the scope of dialysis by the implementation of cheaper alternatives.