A novel inhibitor of p75-neurotrophin receptor improves functional outcomes in two models of traumatic brain injury.

The p75 neurotrophin receptor is important in multiple physiological actions including neuronal survival and neurite outgrowth during development, and after central nervous system injury. We have discovered a novel piperazine-derived compound, EVT901, which interferes with p75 neurotrophin receptor oligomerization through direct interaction with the first cysteine-rich domain of the extracellular region. Using ligand binding assays with cysteine-rich domains-fused p75 neurotrophin receptor, we confirmed that EVT901 interferes with oligomerization of full-length p75 neurotrophin receptor in a dose-dependent manner. Here we report that EVT901 reduces binding of pro-nerve growth factor to p75 neurotrophin receptor, blocks pro-nerve growth factor induced apoptosis in cells expressing p75 neurotrophin receptor, and enhances neurite outgrowth in vitro Furthermore, we demonstrate that EVT901 abrogates p75 neurotrophin receptor signalling by other ligands, such as prion peptide and amyloid-β. To test the efficacy of EVT901 in vivo, we evaluated the outcome in two models of traumatic brain injury. We generated controlled cortical impacts in adult rats. Using unbiased stereological analysis, we found that EVT901 delivered intravenously daily for 1 week after injury, reduced lesion size, protected cortical neurons and oligodendrocytes, and had a positive effect on neurological function. After lateral fluid percussion injury in adult rats, oral treatment with EVT901 reduced neuronal death in the hippocampus and thalamus, reduced long-term cognitive deficits, and reduced the occurrence of post-traumatic seizure activity. Together, these studies provide a new reagent for altering p75 neurotrophin receptor actions after injury and suggest that EVT901 may be useful in treatment of central nervous system trauma and other neurological disorders where p75 neurotrophin receptor signalling is affected

Defining the organizational structure of dopamine and muscarninic acetylcholine receptors

No abstract available

Inflammasomes in neuroinflammatory and neurodegenerative diseases

Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid-beta, alpha-synuclein, and prions, that can activate inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host-derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin (IL)-1 beta and IL-18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS-resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome-targeted strategies that may potentially treat these diseases

Stem Cell-Derived Oligodendroglial Cells for Therapy in Neurological Diseases.

There are an important number of neurological diseases where not neurons but glia are the responsible cells for the degeneration of the nervous system. In the last years, determinant roles for oligodendrocytes (OLs) have been demonstrated not only in myelin generation and maintenance but also for metabolic support of neurons. Oligodendroglial defects lead to brain degeneration in several diseases, supporting the idea that not only endogenous regeneration but also administration of exogenous OL precursors will lead to overcome functional deficits. In this review, we discuss many diseases where OLs play a crucial role, and focus on the different sources and methods to obtain oligodendroglial cells that could be used in cell therapy for myelin-related and oligodendrocyte-deficient diseases

Identification of pathways of degeneration and protection in motor neuron diseases

Motor neuron diseases preferentially affect specific neuronal populations with distinct clinical features even if disease-causing genes are expressed in many cell types. In spinal muscular atrophy (SMA), somatic motor neurons are selectively vulnerable to a deficiency in the broadly expressed survival of motor neuron 1 (SMN1) gene. In amyotrophic lateral sclerosis (ALS), mutations in multiple ubiquitously expressed genes have been identified that result in the same selective vulnerability. However, certain somatic motor neuron groups, including oculomotor and trochlear (CN3/4) neurons, are for unknown reasons relatively resistant to degeneration. We hypothesized that we could use CN3/4 motor neuron resistance as a tool to dissect mechanisms of vulnerability and protection, which would aid in identifying drug targets for the treatment of so far incurable motor neuron diseases. Within this thesis work, we developed a robust method for spatial transcriptomic profiling of closely related neuronal populations that is sensitive down to single cells and can be applied to partly degraded human post-mortem tissues. We called this method LCM-seq (laser capture microscopy coupled with RNA sequencing). We applied LCM-seq to reveal longitudinal changes in gene expression in a mouse model of SMA in order to elucidate distinct adaptation mechanisms of several motor neuron populations that could account for their differential susceptibility. We revealed a common activation of DNA damage response and apoptosis pathways in somatic motor neurons independent of their susceptibility. We furthermore found gene expression changes that were preferential to the resistant CN3/4 motor neurons. Of particular interest were genes that function in regeneration, synaptic vesicle release and those that protect cells from oxidative stress and apoptosis. We speculate that these genes could play a role in the resistance of CN3/4 motor neurons and their manipulation in vulnerable motor neurons could be used to protect these from degeneration. As proof of concept, we further investigated candidates with implications for differential vulnerability that we had previously identified in a transcriptome analysis in the normal rat. We demonstrated a relative conservation across species by confirming the expression patterns of multiple proteins in mouse and human and in health and disease. Moreover, we provided functional evidence that the oculomotor restricted insulin-like growth factor 2 (IGF-2) can rescue vulnerable spinal motor neurons in in vitro and in vivo models of ALS. This indicates that IGF-2 could in part play a role in the preservation of CN3/4 motor neurons in ALS. By combining comprehensive studies in mouse models and the use of human ALS patient tissues as well as patient-derived induced pluripotent stem cell based in vitro assays we could maximize the chance of identifying mechanisms with relevance in human disease. In conclusion, we provide a tool box for transcriptional profiling of neuronal populations with differential vulnerability followed by functional studies in mouse and human aiding in elucidating pathological mechanisms in neurodegenerative diseases, which could lead to the identification of drug targets for the treatment of motor neuron diseases

Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition where loss of motor neurons within the brain and spinal cord leads to muscle atrophy, weakness, paralysis and ultimately death within 3–5 years from onset of symptoms. The specific molecular mechanisms underlying the disease pathology are not fully understood and neuroprotective treatment options are minimally effective. In recent years, stem cell transplantation as a new therapy for ALS patients has been extensively investigated, becoming an intense and debated field of study. In several preclinical studies using the SOD1G93A mouse model of ALS, stem cells were demonstrated to be neuroprotective, effectively delayed disease onset and extended survival. Despite substantial improvements in stem cell technology and promising results in preclinical studies, several questions still remain unanswered, such as the identification of the most suitable and beneficial cell source, cell dose, route of delivery and therapeutic mechanisms. This review will cover publications in this field and comprehensively discuss advances, challenges and future direction regarding the therapeutic potential of stem cells in ALS, with a focus on mesenchymal stem cells. In summary, given their high proliferation activity, immunomodulation, multi-differentiation potential, and the capacity to secrete neuroprotective factors, adult mesenchymal stem cells represent a promising candidate for clinical translation. However, technical hurdles such as optimal dose, differentiation state, route of administration, and the underlying potential therapeutic mechanisms still need to be assessed

The role of Insulin-like Growth Factors (IGFs) and IGF-binding proteins in the nervous system

The insulin-like growth factors (IGF-I and IGF-II) and their receptors are widely expressed in nervous tissue from early embryonic life. They also cross the blood brain barriers by active transport, and their regulation as endocrine factors therefore differs from other tissues. In brain, IGFs have paracrine and autocrine actions that are modulated by IGF-binding proteins and interact with other growth factor signalling pathways. The IGF system has roles in nervous system development and maintenance. There is substantial evidence for a specific role for this system in some neurodegenerative diseases, and neuroprotective actions make this system an attractive target for new therapeutic approaches. In developing new therapies, interaction with IGF-binding proteins and other growth factor signalling pathways should be considered. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research

Neural stem cell transplantation for neurodegenerative diseases

Neurodegenerative diseases are disabling and fatal neurological disorders that currently lack effective treatment. Neural stem cell (NSC) transplantation has been studied as a potential therapeutic approach and appears to exert a beneficial effect against neurodegeneration via different mechanisms, such as the production of neurotrophic factors, decreased neuroinflammation, enhanced neuronal plasticity and cell replacement. Thus, NSC transplantation may represent an effective therapeutic strategy. To exploit NSCs\u2019 potential, some of their essential biological characteristics must be thoroughly investigated, including the specific markers for NSC subpopulations, to allow profiling and selection. Another key feature is their secretome, which is responsible for the regulation of intercellular communication, neuroprotection, and immunomodulation. In addition, NSCs must properly migrate into the central nervous system (CNS) and integrate into host neuronal circuits, enhancing neuroplasticity. Understanding and modulating these aspects can allow us to further exploit the therapeutic potential of NSCs. Recent progress in gene editing and cellular engineering techniques has opened up the possibility of modifying NSCs to express select candidate molecules to further enhance their therapeutic effects. This review summarizes current knowledge regarding these aspects, promoting the development of stem cell therapies that could be applied safely and effectively in clinical settings