Nervous System Immune Cells

There are distinct populations of central nervous system immune cells comparing states of health, aging, and disease Alzheimer's disease and multiple sclerosis). This may assist in devising new therapeutic strategies against those diseases as well as giving insights into the human aging process. Abstract:

Individual reports suggest that the central nervous system (CNS) contains multiple immune cell types with diverse roles in tissue homeostasis, immune defense, and neurological diseases. It has been challenging to map leukocytes across the entire brain, and in particular in pathology, where phenotypic changes and influx of blood-derived cells prevent a clear distinction between reactive leukocyte populations. Here, we applied high-dimensional single-cell mass and fluorescence cytometry, in parallel with genetic fate mapping systems, to identify, locate, and characterize multiple distinct immune populations within the mammalian CNS. Using this approach, we revealed that microglia, several subsets of border-associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease-specific transformations in the immune microenvironment during aging and in models of Alzheimer's disease and multiple sclerosis. Together, these data and the described framework provide a resource for the study of disease mechanisms, potential biomarkers, and therapeutic targets in CNS disease. 

Screening For Factors Influencing Neurodegenerative Diseases

Screening for factors influencing neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia, shows the importance of modifiers of an important mechanism of those diseases: hexanucleotide-repeat expansions in the C9ORF72 gene that result in toxic dipeptide-repeat proteins that aggregate – abnormal protein aggregation being a key feature of many nervous system-related diseases. This may have implications for treatment.  Abstract:

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases.

Preventing Neuronal Disease Through The Microbiota

Once again, modifying the microbiota through diet can prevent neuroimmune and neuroinflammatory disease.

The gut-brain-axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut-microbiota-brain axis. Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases. In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota, and in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease.

Genetic Structure Affected By Maternal Care (In Mice)

Early life experiences, such as maternal care, alters the genetic structure in neurons in mice, with mobile genetic elements seemingly responsible.  Does the same apply to humans?  Abstract:

The brain is a genomic mosaic owing to somatic mutations that arise throughout development. Mobile genetic elements, including retrotransposons, are one source of somatic mosaicism in the brain. Retrotransposition may represent a form of plasticity in response to experience. Here, we use droplet digital polymerase chain reaction to show that natural variations in maternal care mediate the mobilization of long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons in the hippocampus of the mouse brain. Increasing the amount of maternal care blocks the accumulation of L1. Maternal care also alters DNA methylation at YY1 binding sites implicated in L1 activation and affects expression of the de novo methyltransferase DNMT3a. Our observations indicate that early life experience drives somatic variation in the genome via L1 retrotransposons.

Iron Deficiency Problems: More Than Just Anemia

By Alchemist-hp (talk) (www.pse-mendelejew.de) - Own work, FAL, https://commons.wikimedia.org/w/index.php?curid=10115787

Iron deficiency can have harmful effects other than just anemia (which is bad enough); there can be problems with immune and nervous system function, as well as other negative effects.  Abstract:

OBJECTIVE:

To consider the key implications of iron deficiency for biochemical and physiological functions beyond erythropoiesis.

METHODS:

PubMed was searched for relevant journal articles published up to August 2017.

RESULTS:

Anemia is the most well-recognized consequence of persisting iron deficiency, but various other unfavorable consequences can develop either before or concurrently with anemia. Mitochondrial function can be profoundly disturbed since iron is a cofactor for heme-containing enzymes and non-heme iron-containing enzymes in the mitochondrial electron transport chain. Biosynthesis of heme and iron-sulfur clusters in the mitochondria is inhibited, disrupting synthesis of compounds such as hemoglobin, myoglobin, cytochromes and nitric oxide synthase. The physiological consequences include fatigue, lethargy and dyspnea; conversely iron repletion in iron-deficient individuals has been shown to improve exercise capacity. The myocardium, with its high energy demands, is particularly at risk from the effects of iron deficiency. Randomized trials have found striking improvements in disease severity in anemic but also non-anemic chronic heart failure patients with iron deficiency after iron therapy. In vitro and preclinical studies have demonstrated that iron is required by numerous enzymes involved in DNA replication and repair, and for normal cell cycle regulation. Iron is also critical for immune cell growth, proliferation and differentiation and for specific cell-mediated effector pathways. Observational studies have shown that iron-deficient individuals have defective immune function, particularly T-cell immunity, but more evidence is required. Preclinical models have demonstrated abnormal myelogenesis, brain cell metabolism, neurotransmission and hippocampal formation in iron-deficient neonates and young animals. In humans, iron deficiency anemia is associated with poorer cognitive and motor skills. However, the impact of iron deficiency without anemia is less clear.

CONCLUSION:

The widespread cellular and physiological effects of iron deficiency highlight the need for early detection and treatment of iron deficiency, both to ameliorate these non-erythropoietic effects and to avoid progression to iron deficiency anemia.

Dietary Polyphenols And Preventing Cognitive Decline With Aging

Dietary polyphenols, by affecting cell signaling, can prevent declining nerve growth in adults and counteract cognitive decline due to age.  Such dietary components are found at high levels in fruit, but not in doughnuts, by the way, not that I want to “fat shame” anyone.  Abstract:

The increased number of elderly people worldwide poses a major medical and socio-economic challenge: the search of strategies to combat the consequences of the aging process. Oxidative stress and inflammation have been pointed out as the leading causes of brain aging, which in turn alters the functionality of brain. In this context, decline in adult neurogenesis (AN), due to modifications in the neural progenitor stem cells (NSCs) and their microenvironment, is among the aging alterations contributing to cognitive decline. Therefore, the consumption or administration of antioxidant and anti-inflammatory molecules, such as dietary polyphenols, is under study as a potential beneficial strategy for preventing brain aging alterations including AN decline. Polyphenols, through their antioxidant and anti-inflammatory properties, modulate several cascades and effectors involved in the regulation of AN (e.g., SIRT1, Wnt, NF-κB and Nrf2, among others). This work summarizes the latest discoveries regarding the mechanisms whereby polyphenols preserve AN and counteract the cognitive decline present in aging.