Chronological versus immunological aging: Immune rejuvenation to arrest cognitive decline.

The contemporary understanding that the immune response significantly supports higher brain functions has emphasized the notion that the brain's condition is linked in a complex manner to the state of the immune system. It is therefore not surprising that immunity is a key factor in shaping brain aging. In this perspective article, we propose amending the Latin phrase "mens sana in corpore sano" ("a healthy mind in a healthy body") to "a healthy mind in a healthy immune system.

Monocyte-derived macrophages act as reinforcements when microglia fall short in Alzheimer's disease.

The central nervous system (CNS) is endowed with its own resident innate immune cells, the microglia. They constitute approximately 10% of the total cells within the CNS parenchyma and act as 'sentinels', sensing and mitigating any deviation from homeostasis. Nevertheless, under severe acute or chronic neurological injury or disease, microglia are unable to contain the damage, and the reparative activity of monocyte-derived macrophages (MDMs) is required.

The immune and metabolic milieu of the choroid plexus as a potential target in brain protection.

The brain's choroid plexus (CP), which operates as an anatomical and functional 'checkpoint', regulates the communication between brain and periphery and contributes to the maintenance of healthy brain homeostasis throughout life. Evidence from mouse models and humans reveals a link between loss of CP checkpoint properties and dysregulation of the CP immune milieu as a conserved feature across diverse neurological conditions. In particular, we suggest that an imbalance between different immune signals at the CP, including CD4 T cell-derived cytokines, type-I interferon, and complement components, can perpetuate brain inflammation and cognitive deterioration in aging and neurodegeneration.

A virally encoded high-resolution screen of cytomegalovirus dependencies.

Genetic screens have transformed our ability to interrogate cellular factor requirements for viral infections, but most current approaches are limited in their sensitivity, biased towards early stages of infection and provide only simplistic phenotypic information that is often based on survival of infected cells. Here, by engineering human cytomegalovirus to express single guide RNA libraries directly from the viral genome, we developed virus-encoded CRISPR-based direct readout screening (VECOS), a sensitive, versatile, viral-centric approach that enables profiling of different stages of viral infection in a pooled format. Using this approach, we identified hundreds of host dependency and restriction factors and quantified their direct effects on viral genome replication, viral particle secretion and infectiousness of secreted particles, providing a multi-dimensional perspective on virus-host interactions.

Bridging anatomical gaps between brain and immune system.

It is increasingly clear that the central nervous system (CNS) relies significantly on both adaptive and innate immune cells for its repair and lifelong maintenance. These interactions hold profound implications for brain aging and neurodegeneration. Recent work by Smyth et al.

Identification of senescent, TREM2-expressing microglia in aging and Alzheimer's disease model mouse brain.

Alzheimer's disease (AD) and dementia in general are age-related diseases with multiple contributing factors, including brain inflammation. Microglia, and specifically those expressing the AD risk gene TREM2, are considered important players in AD, but their exact contribution to pathology remains unclear. In this study, using high-throughput mass cytometry in the 5×FAD mouse model of amyloidosis, we identified senescent microglia that express high levels of TREM2 but also exhibit a distinct signature from TREM2-dependent disease-associated microglia (DAM).

Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis.

The choroid plexus (CP) plays a key role in remotely controlling brain function in health, aging, and disease. Here, we report that CP epithelial cells express the brain-specific cholesterol 24-hydroxylase (CYP46A1) and that its levels are decreased under different mouse and human brain conditions, including amyloidosis, aging, and SARS-CoV-2 infection. Using primary mouse CP cell cultures, we demonstrate that the enzymatic product of CYP46A1, 24(S)-hydroxycholesterol, downregulates inflammatory transcriptomic signatures within the CP, found here to be elevated across multiple neurological conditions.

No democracy, no academia.

Over the past 30 weeks, Israel has been undergoing an upheaval marked by unprecedented attacks by the government on the independence of its judiciary, attorney general, government legal advisers, police, military, public broadcasting, and religious freedom. This assault on democratic institutions and principles is an imminent threat to Israeli academia, which relies on a solid democratic foundation. In response, universities, academics, and students have emerged as key proponents of ongoing protests under the banner, "No democracy, no academia.

Rethinking human cytomegalovirus latency reservoir.

Human cytomegalovirus (HCMV) is a prevalent herpesvirus, infecting the majority of the human population. Like other herpesviruses, it causes lifelong infection through the establishment of latency. Although reactivation from latency can cause significant morbidity and mortality in immunocompromised hosts, our understanding of HCMV latency and how it is maintained remains limited.

Transforming the understanding of brain immunity.

Contemporary studies have completely changed the view of brain immunity from envisioning the brain as isolated and inaccessible to peripheral immune cells to an organ in close physical and functional communication with the immune system for its maintenance, function, and repair. Circulating immune cells reside in special niches in the brain's borders, the choroid plexus, meninges, and perivascular spaces, from which they patrol and sense the brain in a remote manner. These niches, together with the meningeal lymphatic system and skull microchannels, provide multiple routes of interaction between the brain and the immune system, in addition to the blood vasculature.

N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer's disease mouse model.

Systemic immunity supports lifelong brain function. Obesity posits a chronic burden on systemic immunity. Independently, obesity was shown as a risk factor for Alzheimer's disease (AD).

Molecular characterization of human cytomegalovirus infection with single-cell transcriptomics.

Human cytomegalovirus (HCMV) can result in either productive or non-productive infection, with the latter potentially leading to viral latency. The molecular factors dictating these outcomes are poorly understood. Here we used single-cell transcriptomics to analyse HCMV infection progression in monocytes, which are latently infected, and macrophages, considered to be permissive for productive infection.

The type I interferon antiviral response in the choroid plexus and the cognitive risk in COVID-19.

The type I interferon (IFN) response is the body's typical immune defense against viruses. Previous studies linked high expression of genes encoding type I IFNs in the brain's choroid plexus to cognitive decline under virus-free conditions in aging and neurodegeneration. Multiple reports have documented persisting cognitive symptoms following recovery from COVID-19.

Microglia states and nomenclature: A field at its crossroads.

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions.

The brain-immune ecosystem: Implications for immunotherapy in defeating neurodegenerative diseases.

Recent functional and anatomical discoveries of brain-immune relationships have overturned previous beliefs regarding the brain's immune privilege. Here, we propose that the brain and immune cells at its borders operate as an "ecosystem" to support the brain's robustness and resilience. Modulation of this ecosystem can be harnessed in the clinic.

A shared disease-associated oligodendrocyte signature among multiple CNS pathologies.

Alzheimer's disease (AD) is a complex neurodegenerative disease, perturbing neuronal and non-neuronal cell populations. In this study, using single-cell transcriptomics, we mapped all non-immune, non-neuronal cell populations in wild-type and AD model (5xFAD) mouse brains. We identified an oligodendrocyte state that increased in association with brain pathology, which we termed disease-associated oligodendrocytes (DOLs).

Ep300 sequestration to functionally distinct glucocorticoid receptor binding loci underlie rapid gene activation and repression.

The rapid transcriptional response to the transcription factor, glucocorticoid receptor (GR), including gene activation or repression, is mediated by the spatial association of genes with multiple GR binding sites (GBSs) over large genomic distances. However, only a minority of the GBSs have independent GR-mediated activating capacity, and GBSs with independent repressive activity were rarely reported. To understand the positive and negative effects of GR we mapped the regulatory environment of its gene targets.

Parsing the role of NSP1 in SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to shutoff of protein synthesis, and nsp1, a central shutoff factor in coronaviruses, inhibits cellular mRNA translation. However, the diverse molecular mechanisms employed by nsp1 as well as its functional importance are unresolved. By overexpressing various nsp1 mutants and generating a SARS-CoV-2 mutant, we show that nsp1, through inhibition of translation and induction of mRNA degradation, targets translated cellular mRNA and is the main driver of host shutoff during infection.

The vicious cycle governing the brain-immune system relationship in neurodegenerative diseases.

For decades, neurodegenerative diseases were thought to be caused by the accumulation of toxic compounds, exacerbated by local inflammation, which together lead to neuronal loss and cognitive impairment . An additional factor that was long overlooked , is the role of the systemic immune system, which provides a defense mechanism against internal and external intruders in all bodily tissues. The evolving understanding of the life-long cross-talk between the CNS and the immune system led to an awareness of the function of systemic adaptive immunity in containing emerging destructive factors within the brain.

Temporal dynamics of HCMV gene expression in lytic and latent infections.

During productive human cytomegalovirus (HCMV) infection, viral genes are expressed in a coordinated cascade that conventionally relies on the dependencies of viral genes on protein synthesis and viral DNA replication. By contrast, the transcriptional landscape of HCMV latency is poorly understood. Here, we examine viral gene expression dynamics during the establishment of both productive and latent HCMV infections.

Parsing the role of NSP1 in SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 19 (COVID-19) pandemic. Despite its urgency, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis and its ability to antagonize innate immune responses. SARS-CoV-2 leads to shutoff of cellular protein synthesis and over-expression of nsp1, a central shutoff factor in coronaviruses, inhibits cellular gene translation.

Alzheimer's disease modification mediated by bone marrow-derived macrophages via a TREM2-independent pathway in mouse model of amyloidosis.

Microglia and monocyte-derived macrophages (MDM) are key players in dealing with Alzheimer's disease. In amyloidosis mouse models, activation of microglia was found to be TREM2 dependent. Here, using Trem25xFAD mice, we assessed whether MDM act via a TREM2-dependent pathway.