Early-life IL-4 administration induces long-term changes in microglia in the cerebellum and prefrontal cortex.

Microglia are crucial for brain development and their function can be impacted by postnatal insults, such as early-life allergies. These are characterized by an upregulation of interleukin (IL)-4 levels. Allergies share a strong comorbidity with Autism Spectrum Disorders (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD).

IL-4 shapes microglia-dependent pruning of the cerebellum during postnatal development.

Interleukin-4 (IL-4) is a type 2 cytokine with pleiotropic functions in adaptive immunity, allergies, and cognitive processes. Here, we show that low levels of IL-4 in the early postnatal stage delineate a critical period in which microglia extensively prune cerebellar neurons. Elevating the levels of this cytokine via peripheral injection, or using a mouse model of allergic asthma, leads to defective pruning, permanent increase in cerebellar granule cells, and circuit alterations.

Microglia-dependent remodeling of neuronal circuits.

Microglia are tissue-resident macrophages responsible for the surveillance, neuronal support, and immune defense of the brain parenchyma. Recently, the role played by microglia in the formation and function of neuronal circuits has garnered substantial attention. During development, microglia have been shown to engulf neuronal precursors and participate in pruning mechanisms while, in the mature brain, they influence synaptic signaling, provide trophic support and shape synaptic plasticity.

The old guard: Age-related changes in microglia and their consequences.

Among all major organs, the brain is one of the most susceptible to the inexorable effects of aging. Throughout the last decades, several studies in human cohorts and animal models have revealed a plethora of age-related changes in the brain, including reduced neurogenesis, oxidative damage, mitochondrial dysfunction and cell senescence. As the main immune effectors and first responders of the nervous tissue, microglia are at the center of these events.

Social subordination induced by early life adversity rewires inhibitory control of the prefrontal cortex via enhanced Npy1r signaling.

Social hierarchies are present in most mammalian species. In nature, hierarchies offer a tradeoff between reduction of in-group fighting between males, at the expense of an asymmetric sharing of resources. Early life experiences and stress are known to influence the rank an individual attains in adulthood, but the associated cellular and synaptic alterations are poorly understood.

Abnormal mGluR-mediated synaptic plasticity and autism-like behaviours in Gprasp2 mutant mice.

Autism spectrum disorder (ASD) is characterized by dysfunction in social interactions, stereotypical behaviours and high co-morbidity with intellectual disability. A variety of syndromic and non-syndromic neurodevelopmental disorders have been connected to alterations in metabotropic glutamate receptor (mGluR) signalling. These receptors contribute to synaptic plasticity, spine maturation and circuit development.

Roles of Microglial and Monocyte Chemokines and Their Receptors in Regulating Alzheimer's Disease-Associated Amyloid-β and Tau Pathologies.

Chemokines and their receptors have been shown to affect amyloid-β (Aβ) and tau pathologies in mouse models of Alzheimer's disease (AD) by regulating microglia and monocyte-associated neuroinflammation, microglial movement and monocyte recruitment into the brain. These cells in turn can promote and mediate Aβ phagocytosis and degradation and tau phosphorylation. In this review we discuss published work in this field in mouse models of AD and review what is known about the contributions of microglial and monocyte chemokines and their receptors to amyloid and tau pathologies.

Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases.

Objective: Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel.

Quantifying miRNA Deregulation in Alzheimer's Disease.

Analysis of miRNA expression in circulating immune cells, such as monocytes, using qRT-PCR arrays, allows the quantification of a wide range of miRNAs in easily accessible biosamples from Alzheimer's disease patients. This technique enables the identification of differentially expressed miRNAs and provides important clues for the discovery of new miRNA-based biomarkers. Here we describe how to isolate a specific lymphocyte population from human blood samples, CD14 monocytes, and how to extract total RNA, containing short RNAs, from these cells, transcribe the RNA into cDNA and quantify a pre-set of specific miRNAs using customizable PCR plates of 96 or 384 wells.

miRNAs: New Biomarkers and Therapeutic Targets in Dementia.

Background: Dementia is a complex pathological state that affects millions of individuals worldwide and is responsible for a huge socioeconomic burden, making it a major health concern of current times. Given the impact of dementia in both patients and caregivers, it is crucial to fully clarify the molecular mechanisms underlying dementia-associated disorders, since without this knowledge our ability to correctly diagnose and treat these diseases is severely hampered.

Methods: Epigenetic mechanisms, such as miRNA-mediated post-transcriptional regulation, have been reported to play a role in dementia pathogenesis.

MicroRNA deregulation and chemotaxis and phagocytosis impairment in Alzheimer's disease.

Introduction: Mononuclear phagocytes play a critical role during Alzheimer's disease (AD) pathogenesis due to their contribution to innate immune responses and amyloid beta (Aβ) clearance mechanisms.

Methods: Blood-derived monocytes (BDMs) and monocyte-derived macrophages (MDMs) were isolated from blood of AD, mild cognitive impairment (MCI) patients, and age-matched healthy controls for molecular and phenotypic comparisons.

Results: The chemokine/chemokine receptor CCL2/CCR2 axis was impaired in BDMs from AD and MCI patients, causing a deficit in cell migration.

Role of microRNAs in the regulation of innate immune cells under neuroinflammatory conditions.

MiRNAs are short, evolutionary conserved noncoding RNA molecules with the ability to control the magnitude of inflammation. The immunosuppressive nature of the brain is sustained by miRNA-dependent regulation of microglial cells, which become activated under neuroinflammatory conditions, such as brain injury and neurodegeneration. The pro-inflammatory and suppressive role of the most studied neuroimmune miRNAs, miR-155 and miR-146a, has been recently challenged.

Early miR-155 upregulation contributes to neuroinflammation in Alzheimer's disease triple transgenic mouse model.

MicroRNAs (miRNAs) have emerged as a class of small, endogenous, regulatory RNAs that exhibit the ability to epigenetically modulate the translation of mRNAs into proteins. This feature enables them to control cell phenotypes and, consequently, modify cell function in a disease context. The role of inflammatory miRNAs in Alzheimer's disease (AD) and their ability to modulate glia responses are now beginning to be explored.

miR-155 modulates microglia-mediated immune response by down-regulating SOCS-1 and promoting cytokine and nitric oxide production.

Innate immunity constitutes the first line of defence against both external and endogenous threats in the brain, and microglia cells are considered key mediators of this process. Recent studies have shown that microRNAs (miRNAs) may play a determinant role in the regulation of gene expression during innate immune responses. The major goal of this work was to investigate the contribution of a specific miRNA - miR-155 - to the modulation of the microglia-mediated immune response.