Activation of glial cells has been proposed to contribute to neuronal dysfunction and neuronal cell death in Alzheimer's disease. In this study, we attempt to determine some of the effects of secreted factors from activated murine N-11 microglia on viability and morphology of neurons using the differentiated neuroblastoma cell line Neuro2a. Microglia were activated either by lipopolysaccharide (LPS), bacterial cell wall proteoglycans, or advanced glycation endproducts (AGEs), protein-bound sugar oxidation products. At high LPS or AGE concentrations, conditioned medium from microglia caused neuronal cell death in a dose-dependent manner. At sublethal LPS or AGE concentrations, conditioned media inhibited retinoic acid-induced neurite outgrowth and stimulated retraction of already extended neurites. Among the many possible secreted factors, the contribution of NO or NO metabolites in the cytotoxicity of conditioned medium was investigated. Cell death and changes in neurite morphology were partly reduced when NO production was inhibited by nitric oxide synthase inhibitors. The results suggest that even in the absence of significant cell death, inflammatory processes, which are partly transmitted via NO metabolites, may affect intrinsic functions of neurons such as neurite extension that are essential components of neuronal morphology and thus may contribute to degenerative changes in Alzheimer's disease.
Amphoterin, a major form of HMG (high mobility group) 1 proteins, is highly expressed in immature and malignant cells. A role in cell motility is suggested by the ability of amphoterin to promote neurite extension through RAGE (receptor of advanced glycation end products), an immunoglobulin superfamily member that communicates with the GTPases Cdc42 and Rac. We show here that cell contact with the laminin matrix induces accumulation of both amphoterin mRNA and protein close to the plasma membrane, which is accompanied by extracellular export of amphoterin. A role for amphoterin in extracellular matrix-dependent cell regulation is further suggested by the finding that specific decrease of amphoterin mRNA and protein, using antisense oligonucleotides transfected into cells, inhibits cell migration to laminin in a transfilter assay whereas the oligonucleotides in the culture medium have no effect. Moreover, affinity-purified anti-amphoterin antibodies inhibit cell migration to laminin, supporting an extracellular role for the endogenous amphoterin in cell motility. The finding that amphoterin expression is more pronounced in cells with a motile phenotype as compared to cells of dense cultures, is consistent with the results of the cell migration assays. Our results strongly suggest that amphoterin is a key player in the migration of immature and transformed cells.
During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain’s myeloid cells for the treatment of ICH.
Clinical trials in neurodegenerative disorders have been associated with high rate of failures, while in oncology, the implementation of precision medicine and focus on genetically defined subtypes of disease and targets for drug development have seen an unprecedented success. With more than 20 genes associated with Parkinson’s disease (PD), most of which are highly penetrant and often cause early onset or atypical signs and symptoms, and an increasing understanding of the associated pathophysiology culminating in dopaminergic neurodegeneration, applying the technologies and designs into the field of neurodegeneration seems a logical step. This review describes some of the methods used in oncology clinical trials and some attempts in Parkinson’s disease and the potential of further implementing genetics, biomarkers and smart clinical trial designs in this disease area.
In Alzheimer's disease (AD), loss of neurons and synapses parallels the formation of neurofibrillary tangles, protein aggregates mainly composed of hyperphosphorylated and aggregated Tau protein. Tau is mostly a cytosolic protein but can also be secreted by neurons. Cell-to-cell transfer of misfolded Tau protein plays a key role in the spread of neurofibrillary pathology between brain regions in AD and other tauopathies. Advances in genome-wide technologies have identified a large number of genetic risk factors for lateonset AD (LOAD). Currently, it remains unknown if genetic factors influence disease risk or progression rate by altering cell-to-cell propagation of Tau. Several LOAD risk genes are functionally associated with endocytic trafficking providing a potential link to Tau secretion and uptake. Recently, a LOAD risk gene FRMD4A was shown to regulate Tau secretion via a pathway linked to presynaptic vesicle machinery and polarity signaling. Tau release is linked to neuronal activity, and genetic factors that affect presynaptic vesicle release in the aging brain may also influence disease progression in AD and other tauopathies. In this mini review, we summarize the recent literature with a focus on the role of FRMD4A-cytohesin-Arf6 pathway and presynaptic vesicle machinery in the secretion of Tau.
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