Neuroscience

Researchers at Boston University School of Medicine (BUSM) led by Carmela Abraham, PhD, professor of biochemistry, along with Cidi Chen, PhD, and other collaborators, report that the protein Klotho plays an important role in the health of myelin, the insulating material allowing for the rapid communication between nerve cells. These findings, which appear online in Journal of Neuroscience, may lead to new therapies for multiple sclerosis (MS) and Alzheimer’s disease (AD), in which white matter abnormalities are also common but have been largely ignored.

MS is an inflammatory disease which damages the fatty myelin sheaths around the axons of the brain and spinal cord. This destruction, loss or scarring of the sheaths results in a broad spectrum of symptoms. Disease onset usually occurs in young adults, most commonly women.

In MS the myelin is attacked by the immune system and may not be completely restored by myelin-producing cells (mature oligodendrocytes). The researchers discovered that the addition of Klotho protein to immature oligodendrocytes causes them to mature and manufacture proteins needed for the production of healthy myelin.

"These results taken together indicate that Klotho could become a drug target for multiple sclerosis and other white matter diseases, including AD," explained Abraham.

Abraham and her colleagues have identified, and are working on optimizing, a number of small molecules that could form the basis for the development of therapeutic drugs, which would increase the amount of Klotho protein in the brain.

Since Klotho is not only an age suppressor but also a tumor suppressor, as shown by other research groups, interventions with Klotho-enhancing drugs may solve some of the most treatment-resistant human ailments according to Abraham.

Klotho was named after the Greek Goddess and daughter of Zeus, who spins the thread of life. Abraham’s lab was the first to publish (in 2008) that Klotho levels in the brain decrease with age.

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Testosterone and its derivatives could constitute an efficient treatment against myelin diseases such as multiple sclerosis, reveals a study by researchers from the Laboratoire d’Imagerie et de Neurosciences Cognitives (CNRS/Université de Strasbourg), in collaboration in particular with the “Neuroprotection et Neurorégénération: Molécules Neuroactives de Petite Taille” unit (Inserm/Université Paris-Sud). Myelin composes the sheaths that protect the nerve fibers and allow the speed of nerve impulses to be increased. A deficit in the production of myelin or its destruction cause serious illnesses for which there is no curative treatment. The researchers have shown that in mice brains whose nerve fibers have been demyelinated, testosterone and a synthetic analog induce the regeneration of oligodendrocytes, the cells responsible for myelination, and that they stimulate remyelination. This work is published on January in the journal Brain.

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Scientists have found an early step in how the brain’s inhibitory cells get excited. A natural balance of excitement and inhibition keeps the brain from firing electrical impulses randomly and excessively, resulting in problems such as schizophrenia and seizures. However excitement is required to put on the brakes.  

“When the inhibitory neuron is excited, its job is to suppress whatever activity it touches,” said Dr. Lin Mei, Director of the Institute of Molecular Medicine and Genetics at the Medical College of Georgia at Georgia Regents University and corresponding author of the study in Nature Neuroscience.  

Mei and his colleagues found that the protein erbin, crucial to brain development, is critical to the excitement.

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Synapse development is promoted by a variety of cell adhesion molecules that connect neurons and organize synaptic proteins. Many of these adhesion molecules are linked to neurodevelopmental disorders; mutations in neuroligin and neurexin proteins, for example, are associated with autism and schizophrenia. According to a study in The Journal of Cell Biology, another family of proteins linked to these disorders regulates the function of neuroligins and neurexins in order to suppress the development of inhibitory synapses.

Like neurexins and neuroligins, the neuronal proteins MDGA1 and MDGA2 have been linked to autism and schizophrenia, but their function in neurodevelopment was unknown. Both MDGA proteins localize to the plasma membrane, and their extracellular domains are similar to those of cell adhesion molecules. On the other hand, postsynaptic neuroligin proteins are known to help synapses form by associating with neurexins on presynaptic membranes. Neuroligin-2 specifically boosts the development of inhibitory synapses, whereas neuroligin-1 promotes the development of excitatory synapses.

Ann Marie Craig and colleagues from the University of British Columbia investigated the function of MDGAs using co-culture assays, in which postsynaptic proteins like neuroligin-1 or -2 are expressed in non-neuronal cells and then tested for their ability to induce presynaptic differentiation in neighboring neurons. MDGA1 didn’t promote synapse formation in these assays. Instead, it inhibited the ability of neuroligin-2 to promote synapse development. The researchers found that MDGA1’s extracellular domains bound to neuroligin-2, blocking its association with neurexin. The same domains were sufficient to inhibit neuroligin-2’s synapse-promoting activity. In contrast, MDGA1 didn’t show high affinity binding to, or inhibit the function of, neuroligin-1. This suggested that, by inhibiting neuroligin-2, MDGA1 might specifically suppress the development of inhibitory synapses, so Craig and colleagues investigated MDGA1 function in cultured hippocampal neurons.

“Overexpressing MDGA1 in neurons reduced the density of inhibitory synapses without affecting excitatory synapses,” Craig says. Knocking down MDGA1, on the other hand, increased inhibitory synapse development but had no effect on excitatory synapses.

“I can’t think of any other proteins that specifically suppress inhibitory synapse formation,” says Craig. Indeed, very few proteins in general have been identified as negative regulators of synapse development, compared to the many proteins that are known to promote synaptogenesis. The results suggest that function-altering mutations in the MDGA proteins may disrupt the balance of excitatory and inhibitory synapses in the brain, potentially explaining the development of autism and other neurodevelopmental disorders.

“This puts MDGAs in the same pathway as neurexins and neuroligins and strengthens the evidence for the involvement of synaptic organizing proteins in autism and schizophrenia,” Craig explains. As well as investigating the function of MDGA2, the researchers want to explore the therapeutic potential of MDGA1 inhibitors, not only against autism and schizophrenia but also for the treatment of epilepsy, in which excitatory and inhibitory synapses are also imbalanced.

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Cardiac disease is associated with increased risk of mild cognitive impairment such as problems with language, thinking and judgment — particularly among women with heart disease, a Mayo Clinic study shows. Known as nonamnestic because it doesn’t include memory loss, this type of mild cognitive impairment may be a precursor to vascular and other non-Alzheimer’s dementias, according to the findings published online Monday in JAMA Neurology.

Mild cognitive impairment is an important stage for early detection and intervention in dementia, says lead author, Rosebud Roberts, M.B., Ch.B., a health sciences researcher at Mayo Clinic.

"Prevention and management of cardiac disease and vascular risk factors are likely to reduce the risk," Roberts says.

Researchers evaluated 2,719 people ages 70 to 89 at the beginning of the study and every 15 months after. Of the 1,450 without mild cognitive impairment at the beginning, 669 had heart disease and 59 (8.8 percent) developed nonamenestic mild cognitive impairment; in comparison 34 (4.4 percent) of 781 who did not have heart disease developed nonamenestic mild cognitive impairment.

The association varied by sex; cardiac disease and mild cognitive impairment appeared together more often among women than in men.

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