The neuropathological hallmarks of Alzheimer disease (AD) include “positive” lesions such as amyloid plaques and cerebral amyloid angiopathy, neurofibrillary tangles, and glial responses, and “negative” lesions such as neuronal and synaptic loss. Despite their inherently cross-sectional nature, postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and, consequently, the development of diagnostic criteria that are now used worldwide. In addition, clinicopathological correlation studies have been crucial to generate hypotheses about the pathophysiology of the disease, by establishing that there is a continuum between “normal” aging and AD dementia, and that the amyloid plaque build-up occurs primarily before the onset of cognitive deficits, while neurofibrillary tangles, neuron loss, and particularly synaptic loss, parallel the progression of cognitive decline. Importantly, these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloid PET and volumetric MRI.

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Neuropathological Alterations in Alzheimer Disease

Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

A lineage of myeloid cells independent of Myb and hematopoietic stem cells

OVERVIEW The GRA Marketing Internship Program is offered to students who are interested in gaining valuable work experience through efforts in marketing, membership, sales, and events. Interns work directly to assist the Director of Marketing and Communications on various tasks relating to upcoming GRA events. During this internship, students will work a minimum of 10 hours a week and a maximum of 20 hours a week. Students are encouraged to earn credit for their internship, however this is a paid internship. Students interested in obtaining credit for their internship must consult their academic advisor or the intern coordinator at their academic unit.

Role of WHO.

The concept of multiple macrophage activation states is not new. However, extending this idea to resident tissue macrophages, like microglia, has gained increased interest in recent years. Unfortunately, the research on peripheral macrophage polarization does not necessarily translate accurately to their central nervous system (CNS) counterparts. Even though pro- and anti-inflammatory cytokines can polarize microglia to distinct activation states, the specific functions of these states is still an area of intense debate. This review examines the multiple possible activation states microglia can be polarized to. This is followed by a detailed description of microglial polarization and the functional relevance of this process in both acute and chronic CNS disease models described in the literature. Particular attention is given to utilizing M2 microglial polarization as a potential therapeutic option in treating diseases.

/pdf/neuroinflammation-and-m2-microglia-the-good-the-bad-and-the-hw4av38cgd.pdf

Neuroinflammation and M2 microglia: the good, the bad, and the inflamed.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity both in civilian life and on the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs that were identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies.

/pdf/animal-models-of-traumatic-brain-injury-38xi2wvymz.pdf

Animal models of traumatic brain injury

The 'silent epidemic' of traumatic brain injury (TBI) has been placed in the spotlight as a result of clinical investigations and popular press coverage of athletes and veterans with single or repetitive head injuries. Neuroinflammation can cause acute secondary injury after TBI, and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials. In this Review, we therefore propose a new framework of targeted immunomodulation after TBI for future exploration. Our framework incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structuring our discussion around the dynamics of the immune response to TBI - from initial triggers to chronic neuroinflammation - we consider the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration. We summarize both animal model and human studies, with clinical data explicitly defined throughout this Review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including concepts of inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. Moreover, we highlight findings that could offer novel therapeutic targets for translational and clinical research, assimilate evidence from other brain injury models, and identify outstanding questions in the field.

/pdf/the-far-reaching-scope-of-neuroinflammation-after-traumatic-1mq317cpiv.pdf

The far-reaching scope of neuroinflammation after traumatic brain injury

https://link.springer.com/content/pdf/10.1016%2Fj.nurt.2010.07.002.pdf

Role of microglia in neurotrauma

Traumatic brain injury (TBI) remains one of the leading causes of mortality and morbidity worldwide, yet despite extensive efforts to develop neuroprotective therapies for this devastating disorder there have been no successful outcomes in human clinical trials to date. Following the primary mechanical insult TBI results in delayed secondary injury events due to neurochemical, metabolic and cellular changes that account for many of the neurological deficits observed after TBI. The development of secondary injury represents a window of opportunity for therapeutic intervention to prevent progressive tissue damage and loss of function after injury. To establish effective neuroprotective treatments for TBI it is essential to fully understand the complex cellular and molecular events that contribute to secondary injury. Neuroinflammation is well established as a key secondary injury mechanism after TBI, and it has been long considered to contribute to the damage sustained following brain injury. However, experimental and clinical research indicates that neuroinflammation after TBI can have both detrimental and beneficial effects, and these likely differ in the acute and delayed phases after injury. The key to developing future anti-inflammatory based neuroprotective treatments for TBI is to minimize the detrimental and neurotoxic effects of neuroinflammation while promoting the beneficial and neurotrophic effects, thereby creating optimal conditions for regeneration and repair after injury. This review outlines how post-traumatic neuroinflammation contributes to secondary injury after TBI, and discusses the complex and varied responses of the primary innate immune cells of the brain, microglia, to injury. In addition, emerging experimental anti-inflammatory and multipotential drug treatment strategies for TBI are discussed, as well as some of the challenges faced by the research community to translate promising neuroprotective drug treatments to the clinic.

Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention.

https://www.cohenveteransbioscience.org/wp-content/uploads/2015/10/Loane-Trends-Pharmacol-Sci-2010.pdf

David J. Loane

Papers

The far-reaching scope of neuroinflammation after traumatic brain injury

Role of microglia in neurotrauma

Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention.

Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies.

Microglia in the TBI brain: The good, the bad, and the dysregulated