Is There a Connection between the Metabolism of Copper, Sulfur, and Molybdenum in Alzheimer's Disease? New Insights on Disease Etiology.

Alzheimer's disease (AD) and other forms of dementia was ranked 3rd in both the Americas and Europe in 2019 in a World Health Organization (WHO) publication listing the leading causes of death and disability worldwide. Copper (Cu) imbalance has been reported in AD and increasing evidence suggests metal imbalance, including molybdenum (Mo), as a potential link with AD occurrence.We conducted an extensive literature review of the last 60 years of research on AD and its relationship with Cu, sulfur (S), and Mo at out of range levels.Weanalyzed the interactions among metallic elements' metabolisms;Cu and Mo are biological antagonists, Mo is a sulfite oxidase and xanthine oxidase co-factor, and their low activities impair S metabolism and reduce uric acid, respectively. We found significant evidence in the literature of a new potential mechanism linking Cu imbalance to Mo and S abnormalities in AD etiology: under certain circumstances, the accumulation of Cu not bound to ceruloplasmin might affect the transport of Mo outside the blood vessels, causing a mild Mo deficiency that might lowerthe activity of Mo and S enzymes essential for neuronal activity. The current review provides an updated discussion of the plausible mechanisms combining Cu, S, and Mo alterations in AD.

Inflammatory demyelination alters subcortical visual circuits.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease classically associated with axonal damage and loss; more recently, however, synaptic changes have been recognized as additional contributing factors. An anatomical area commonly affected in MS is the visual pathway; yet, changes other than those associated with inflammatory demyelination of the optic nerve, i.e., optic neuritis, have not been described in detail. METHODS: Adult mice were subjected to a diet containing cuprizone to mimic certain aspects of inflammatory demyelination as seen in MS. Demyelination and inflammation were assessed by real-time polymerase chain reaction and immunohistochemistry. Synaptic changes associated with inflammatory demyelination in the dorsal lateral geniculate nucleus (dLGN) were determined by immunohistochemistry, Western blot analysis, and electrophysiological field potential recordings. RESULTS: In the cuprizone model, demyelination was observed in retinorecipient regions of the subcortical visual system, in particular the dLGN, where it was found accompanied by microglia activation and astrogliosis. In contrast, anterior parts of the pathway, i.e., the optic nerve and tract, appeared largely unaffected. Under the inflammatory demyelinating conditions, as seen in the dLGN of cuprizone-treated mice, there was an overall decrease in excitatory synaptic inputs from retinal ganglion cells. At the same time, the number of synaptic complexes arising from gamma-aminobutyric acid (GABA)-generating inhibitory neurons was found increased, as were the synapses that contain the N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B and converge onto inhibitory neurons. These synaptic changes were functionally found associated with a shift toward an overall increase in network inhibition. CONCLUSIONS: Using the cuprizone model of inflammatory demyelination, our data reveal a novel form of synaptic (mal)adaption in the CNS that is characterized by a shift of the excitation/inhibition balance toward inhibitory network activity associated with an increase in GABAergic inhibitory synapses and a possible increase in excitatory input onto inhibitory interneurons. In addition, our data recognize the cuprizone model as a suitable tool in which to assess the effects of inflammatory demyelination on subcortical retinorecipient regions of the visual system, such as the dLGN, in the absence of overt optic neuritis.

Central nervous system demyelinating diseases: glial cells at the hub of pathology.

Inflammatory demyelinating diseases (IDDs) are among the main causes of inflammatory and neurodegenerative injury of the central nervous system (CNS) in young adult patients. Of these, multiple sclerosis (MS) is the most frequent and studied, as it affects about a million people in the USA alone. The understanding of the mechanisms underlying their pathology has been advancing, although there are still no highly effective disease-modifying treatments for the progressive symptoms and disability in the late stages of disease. Among these mechanisms, the action of glial cells upon lesion and regeneration has become a prominent research topic, helped not only by the discovery of glia as targets of autoantibodies, but also by their role on CNS homeostasis and neuroinflammation. In the present article, we discuss the participation of glial cells in IDDs, as well as their association with demyelination and synaptic dysfunction throughout the course of the disease and in experimental models, with a focus on MS phenotypes. Further, we discuss the involvement of microglia and astrocytes in lesion formation and organization, remyelination, synaptic induction and pruning through different signaling pathways. We argue that evidence of the several glia-mediated mechanisms in the course of CNS demyelinating diseases supports glial cells as viable targets for therapy development.

Expression of GAP-43 during development and after monocular enucleation in the rat superior colliculus.

The retinotectal projection of rodents presents a precise retinotopic organization that develops, from diffuse connections, from the day of birth to post-natal day 10. Previous data had demonstrated that these projections undergo reorganization after retinal lesions, nerve crush and monocular enucleation. The axonal growth seems to be directly related to growth-associated protein-43 (GAP-43) expression, a protein predominantly located in growth cones, which is regulated throughout development. GAP-43 is presented both under non-phosphorylated and phosphorylated (pGAP-43) forms. The phosphorylated form, has been associated to axon growth via polymerization of F-actin, and synaptic enhancement through neurotransmitter release facilitation. Herein we investigated the spatio-temporal expression of GAP-43 in the rat superior colliculus during normal development and after monocular enucleation in different stages of development. Lister Hooded rats ranging from post-natal day 0 to 70 were used for ontogeny studies. Another group of animals were submitted to monocular enucleation at post-natal day 10 (PND10) or PND21. After different survival-times, the animals were sacrificed and the brains processed for either immunohistochemistry or western blotting analysis. Our data show that GAP-43 is expressed in retinotectal axons in early stages of development but remains present in adulthood. Moreover, monocular enucleation leads to an increase in pGAP-43 expression in the deafferented colliculus. Taken together these results suggest a role for pGAP-43 in retinotectal morphological plasticity observed both during normal development and after monocular enucleation.