ABSTRACT
Recent research has provided strong evidence that neurodegeneration may develop from an imbalance between synaptic structural components in the brain. Lately, inhibitory synapses communicating via the neurotransmitters GABA or glycine have come to the center of attention. Increasing evidence suggests that imbalance in the structural composition of inhibitory synapses affect deeply the ability of neurons to communicate effectively over synaptic connections. Progressive failure of synaptic plasticity and memory are thus hallmarks of neurodegenerative diseases. In order to prove that structural changes at synapses contribute to neurodegeneration, we need to visualize single-molecule interactions at synaptic sites in an exact spatial and time frame. This visualization has been restricted in terms of spatial and temporal resolution. New developments in electron microscopy and super-resolution microscopy have improved spatial and time resolution tremendously, opening up numerous possibilities. Here we critically review current and recently developed methods for high-resolution visualization of inhibitory synapses in the context of neurodegenerative diseases. We present advantages, strengths, weaknesses, and current limitations for selected methods in research, as well as present a future perspective. A range of new options has become available that will soon help understand the involvement of inhibitory synapses in neurodegenerative disorders.
Subject(s)
Alzheimer Disease/diagnostic imaging , Brain/diagnostic imaging , Neurons/ultrastructure , Neuroprotective Agents/therapeutic use , Parkinson Disease/diagnostic imaging , Synapses/ultrastructure , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyotrophic Lateral Sclerosis/diagnostic imaging , Amyotrophic Lateral Sclerosis/drug therapy , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Animals , Brain/drug effects , Brain/metabolism , Brain/pathology , Humans , Huntington Disease/diagnostic imaging , Huntington Disease/drug therapy , Huntington Disease/metabolism , Huntington Disease/pathology , Levodopa/therapeutic use , Memantine/therapeutic use , Microscopy, Electron/methods , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/drug therapy , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Neuronal Plasticity/drug effects , Neurons/drug effects , Neurons/metabolism , Neurotransmitter Agents/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Parkinson Disease/pathology , Synapses/drug effects , Synapses/metabolism , Synaptic Transmission/drug effects , Tetrabenazine/therapeutic useABSTRACT
Immunomodulation by adipose-tissue-derived stem cells (ADSCs) is of special interest for the alleviation of damaging inflammatory responses in central nervous system injuries. The present study explored the effects of cerebrospinal fluid (CSF) from traumatic brain injury (TBI) patients on this immunomodulatory potential of ADSCs. CSF conditioning of ADSCs increased messenger RNA levels of both pro- and anti-inflammatory genes compared to controls. Exposure of phorbol-12-myristate-13-acetate-differentiated THP1 macrophages to the secretome of CSF-conditioned ADSCs downregulated both proinflammatory (cyclooxygenase-2, tumor necrosis factor alpha) and anti-inflammatory (suppressor of cytokine signaling 3, interleukin-1 receptor antagonist, and transforming growth factor beta) genes in these cells. Interleukin-10 expression was elevated in both naïve and conditioned secretomes. ADSC secretome treatment, further, induced macrophage maturation of THP1 cells and increased the percentage of CD11b+, CD14+, CD86+, and, to a lesser extent, CD206+ cells. This, moreover, enhanced the phagocytic activity of CD14+ and CD86+ cells, though independently of pre-conditioning. Secretome exposure, finally, also induced a reduction in the percentage of CD192+ adherent cells in cultures of peripheral blood mononuclear cells (PBMCs) from both healthy subjects and TBI patients. This limited efficacy (of both naïve and pre-conditioned secretomes) suggests that the effects of lymphocyte-monocyte paracrine signaling on the fate of cultured PBMCs are strongest upon adherent cell populations.
Subject(s)
Brain Injuries, Traumatic/pathology , Cerebrospinal Fluid , Culture Media, Conditioned , Mesenchymal Stem Cells/physiology , Secretome/immunology , Transplantation Conditioning , Adult , Aged , Case-Control Studies , Cell Culture Techniques , Female , Humans , Inflammation , Leukocytes, Mononuclear/physiology , Macrophages/physiology , Male , Middle Aged , Young AdultABSTRACT
A knowledge management (KM) framework enhances knowledge gathering, sharing, application, and retention within clinical development and enables the effective and successful implementation of a clinical quality management system (QMS). The goal of managing knowledge is to improve organizational performance by getting the right information to the right people at the right time. The concepts of KM have been around for decades but, to date, have not been widely adopted within the clinical development arena. Implementing a structured approach and strategy to managing knowledge can enable more timely and informed decision making, enhance quality and productivity, and ultimately support the delivery of new products to patients. This paper outlines in general terms key elements of a clinical knowledge management (CKM) framework to assist clinical development organizations in understanding its benefits and basic components. Ideas are provided at a high level for flexible approaches and solutions aimed to enhance knowledge gathering, sharing, application, and retention within clinical development.