Inflammation and iron accumulation are present in a variety of neurodegenerative diseases that include Alzheimer's disease and Parkinson's disease. The study of the putative association between inflammation and iron accumulation in central nervous system cells is relevant to understand the contribution of these processes to the progression of neuronal death. In this study, we analyzed the effects of the inflammatory cytokines tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6) and of lipopolysaccharide on total cell iron content and on the expression and abundance of the iron transporters divalent metal transporter 1 (DMT1) and Ferroportin 1 (FPN1) in neurons, astrocytes and microglia obtained from rat brain. Considering previous reports indicating that inflammatory stimuli induce the systemic synthesis of the master iron regulator hepcidin, we identified brain cells that produce hepcidin in response to inflammatory stimuli, as well as hepcidin-target cells. We found that inflammatory stimuli increased the expression of DMT1 in neurons, astrocytes, and microglia. Inflammatory stimuli also induced the expression of hepcidin in astrocytes and microglia, but not in neurons. Incubation with hepcidin decreased the expression of FPN1 in the three cell types. The net result of these changes was increased iron accumulation in neurons and microglia but not in astrocytes. The data presented here establish for the first time a causal association between inflammation and iron accumulation in brain cells, probably promoted by changes in DMT1 and FPN1 expression and mediated in part by hepcidin. This connection may potentially contribute to the progression of neurodegenerative diseases by enhancing iron-induced oxidative damage.

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A proper balance between chemical reduction and oxidation (known as redox balance) is essential for normal cellular physiology. Deregulation in the production of oxidative species leads to DNA damage, lipid peroxidation and aberrant post-translational modification of proteins, which in most cases induces injury, cell death and disease. However, physiological concentrations of oxidative species are necessary to support important cell functions, such as chemotaxis, hormone synthesis, immune response, cytoskeletal remodeling, Ca2+ homeostasis and others. Recent evidence suggests that redox balance regulates actin and microtubule dynamics in both physiological and pathological contexts. Microtubules and actin microfilaments contain certain amino acid residues that are susceptible to oxidation, which reduces the ability of microtubules to polymerize and causes severing of actin microfilaments in neuronal and non-neuronal cells. In contrast, inhibited production of reactive oxygen species (ROS; e.g., due to NOXs) leads to aberrant actin polymerization, decreases neurite outgrowth and affects the normal development and polarization of neurons. In this review, we summarize emerging evidence suggesting that both general and specific enzymatic sources of redox species exert diverse effects on cytoskeletal dynamics. Considering the intimate relationship between cytoskeletal dynamics and trafficking, we also discuss the potential effects of redox balance on intracellular transport via regulation of the components of the microtubule and actin cytoskeleton as well as cytoskeleton-associated proteins, which may directly impact localization of proteins and vesicles across the soma, dendrites and axon of neurons.

Mitochondria-associated membranes (MAMs) are central microdomains that fine-tune bioenergetics by the local transfer of calcium from the endoplasmic reticulum to the mitochondrial matrix. Here, we report an unexpected function of the endoplasmic reticulum stress transducer IRE1α as a structural determinant of MAMs that controls mitochondrial calcium uptake. IRE1α deficiency resulted in marked alterations in mitochondrial physiology and energy metabolism under resting conditions. IRE1α determined the distribution of inositol-1,4,5-trisphosphate receptors at MAMs by operating as a scaffold. Using mutagenesis analysis, we separated the housekeeping activity of IRE1α at MAMs from its canonical role in the unfolded protein response. These observations were validated in vivo in the liver of IRE1α conditional knockout mice, revealing broad implications for cellular metabolism. Our results support an alternative function of IRE1α in orchestrating the communication between the endoplasmic reticulum and mitochondria to sustain bioenergetics. Cellular organelles are no longer conceived as unconnected structures with isolated functions, but as dynamic and integrated compartments. The best-characterized membrane contact sites bridge the endoplasmic reticulum (ER) and mitochondria 1. The ER-the largest organelle in eukaryotic cells-controls protein folding, lipid synthesis and calcium storage. The folding capacity of the ER is constantly challenged by physiological demands and disease states. To sustain proteostasis, cells engage the unfolded protein response (UPR) 2 , a Carreras-Sureda et al.

Cultured neurons obtained from a hypomorphous MAP1B mutant mouse line display a selective and significant inhibition of axon formation that reflects a delay in axon outgrowth and a reduced rate of elongation. This phenomenon is paralleled by decreased microtubule formation and dynamics, which is dramatic at the distal axonal segment, as well as in growth cones, where the more recently assembled microtubule polymer normally predominates. These neurons also have aberrant growth cone formation and increased actin-based protrusive activity. Taken together, this study provides direct evidence showing that by promoting microtubule dynamics and regulating cytoskeletal organization MAP1B has a crucial role in axon formation. INTRODUCTIONNeurons are highly polarized cells that contain a single long axon and multiple dendrites. Polarization occurs when one of the multiple neurites emerging from the cell body initiates a phase of rapid elongation, becoming the axon; the remaining neurites will develop as dendrites Dotti, 1997, 1999;Dotti et al., 1998). Because microtubule assembly and stabilization play an essential role in axon formation (Mitchison and Kirschner, 1989) a great deal of attention has been devoted to identify factors controlling microtubule organization and dynamics in nerve cells. Current evidence favors the view that several of the distinctive properties of neuronal microtubules, such as increased stability and spatial differentiation, arise from the developmentally regulated expression of structural microtubule-associated proteins (MAPs), which are notably abundant in neurons (Maccioni and Cambiazo, 1995). Therefore, it is likely that the expression of these proteins along neuronal development may affect neuronal polarization.MAP1B (Bloom et al., 1995) is the first MAP that is specifically expressed during neural development and that is especially prominent in neurons that are actively extending axons (Calvert and Anderton, 1985;Garner et al., 1990;Fischer and Romano-Clarke, 1991;Ulloa et al., 1993;Black et al., 1994: DiTella et al., 1996Gordon-Weeks and Fischer, 2000). These findings led to the hypothesis that MAP1B might be involved in axon formation by regulating microtubule dynamics. Evidence in favor of this proposal came from antisense experiments showing that MAP1B suppression reduces laminin-promoted axonal elongation (DiTella et al., 1996) and neurite outgrowth in PC12 cells (Brugg et al., 1993). More recently, it was shown that in Drosophila, an MAP1B-like protein is required for proper axonal and dendritic development Roos et al., 2000), and that microscale chromophore-assisted laser inactivation of phosphorylated MAP1B altered growth cone turning behavior in cultured neurons (Mack et al., 2000). The generation of MAP1B mutant mice has also provided additional important information. Despite discrepancies concerning the severity of the effects, all studies demonstrate that MAP1B-deficient mice have an impairment of brain development (Edelman et al., 1996;Takei et al., 1997; GonzalezBillault et...

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC‐CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence‐based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.

The functions of microtubule-associated protein 1B (MAP1B) have historically been linked to the development of the nervous system, based on its very early expression in neurons and glial cells. Moreover, mice in which MAP1B is genetically inactivated have been used extensively to show its role in axonal elongation, neuronal migration, and axonal guidance. In the last few years, it has become apparent that MAP1B has other cellular and molecular functions that are not related to its microtubule-stabilizing properties in the embryonic and adult brain. In this review, we present a systematic review of the canonical and novel functions of MAP1B and propose that, in addition to regulating the polymerization of microtubule and actin microfilaments, MAP1B also acts as a signaling protein involved in normal physiology and pathological conditions in the nervous system.