Monthly Archives: January 2018

Nearly a quarter century ago, a genetic variant known as ApoE4 was identified as a major risk factor for Alzheimer’s disease — one that increases a person’s chances of developing the neurodegenerative disease by up to 12 times. However, it was never clear why the ApoE4 variant was so hazardous.

Now, a study shows that the presence of ApoE4 exacerbates the brain damage caused by toxic tangles of a different Alzheimer’s-associated protein: tau. In the absence of ApoE, tau tangles did very little harm to brain cells.

The findings suggest that targeting ApoE could help prevent or treat the brain damage present in Alzheimer’s disease, for which there are currently no effective therapies.

Alzheimer’s, which affects one in 10 people over age 65, is the most common example of a family of diseases called tauopathies. To find out what effect ApoE variants have on tauopathies, the researchers turned to genetically modified mice that carry a mutant form of human tau prone to forming toxic tangles.

The researchers studied mice that lacked their own version of the mouse ApoE gene or mice with replacements of the three variants of the human ApoE gene: ApoE2, ApoE3 or ApoE4.

By the time the mice were 9 months old, those carrying human ApoE variants had widespread brain damage. ApoE4 mice exhibited the most severe neurodegeneration, and ApoE2 the least. The mice that lacked ApoE entirely showed virtually no brain damage.

Further, the immune cells in the brains of mice with ApoE4 turned on a set of genes related to activation and inflammation much more strongly than those from ApoE3 mice. Immune cells from mice lacking ApoE were barely activated.

Next, the researchers set out to determine whether ApoE in people similarly exacerbates neuronal damage triggered by tau. After studying autopsy samples from 79 people who died from tauopathies, they found that people with ApoE4 had more damage than those that lacked ApoE4.

These findings suggest that decreasing ApoE specifically in the brain could slow or block neurodegeneration, even in people who already have accumulated tau tangles. Most investigational therapies for Alzheimer’s disease have focused on amyloid beta or tau, and none has been successful yet in changing the trajectory of the disease. Targeting ApoE has not yet been tried.

Researchers are hopeful that if their findings are replicated, reducing ApoE in the brain in the early stages of neurodegenerative disease could prevent further neurodegeneration.

Paper: “ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy”
Reprinted from materials provided by Washington University School of Medicine.

Mutations in the human genome may be responsible for many diseases. In the case of Parkinson’s disease (PD), variants of ACMSD (aminocarboxymuconate semialdehyde decarboxylase), may be implicated in PD, but until now, no mutations in ACMSD had been found in any PD patients. In a study in the Journal of Parkinson’s Disease, researchers announce the discovery of a unique mutation in a 74-year-old man with PD. This mutation is not found in the neurologically normal population, and may be the first indication that rare variants in ACMSD alone might increase the risk of PD.

The novel ACMSD mutation was identified during a genetic screening study of 62 PD patients on the island of Menorca, which were matched with 192 ethnicity-matched neurologically normal individuals with no family history of PD. Genetic variants found in these individuals were checked against various databases to identify normal variations observed in other populations. While researchers found mutations already associated with PD, they discovered one novel mutation in the ACMSD gene in a single patient with no family history of PD and none of the known PD-related mutations found in other populations.

The ACMSD gene encodes for an enzyme in the kynurenine pathway, aminocarboxymuconate semialdehyde decarboxylase, involved in the metabolism of tryptophan. Some metabolites of the kynurenine pathway are known to play an important role in the central nervous system in both health and disease states. Specifically, ACMSD activity results in less accumulation of quinolinic acid which is a molecule known to have neurotoxic properties. Not only does quinolinic acid cause “excitotoxicity” (overstimulation of nerve cells leading to their death), but it can also directly activate the immune cells of the brain, i.e. microglia, and thereby trigger inflammation (already known to occur in PD). Therefore, there is a good pathobiological rationale for why reduced levels (due to the mutation) of functional ACMSD can result in the type of neurodegeneration seen in PD brains.

According to the researchers, these results could lead to a better understanding of the disease and, potentially, to the development of new therapeutic strategies.

Researchers have recently discovered a new mechanism for storing information in synapses and a means of controlling the storage process. The breakthrough helps clarify the mystery of the molecular mechanisms of memory and learning processes. The research appears in the journal Nature.

Communication between neurons passes through more than one million billion synapses, tiny structures the tenth of the width of a single hair, in an extremely complex process. Synaptic plasticity, by which synapses adapt to neuronal activity, was discovered nearly 50 years ago. Since then, the scientific community has considered it to be a vital functional component of memorisation and learning.

This new research has helped scientists better understand the basic mechanisms by which information is stored in the brain. Researchers used a combination of techniques based on chemistry, electrophysiology and high-resolution imaging to develop a new method to immobilise receptors at synaptic sites. This method successfully stops receptor movement, making it possible to study the impact of the immobilization on brain activity and learning ability. It provides evidence that receptor movement is essential to synaptic plasticity as a response to intense neuronal activity.

Researchers also explored the direct role of synaptic plasticity in learning. By teaching mice to recognize a specific environment, they show that halting receptor movement can be used to block the acquisition of this type of memory, confirming the role of synaptic plasticity in this process.

The discovery offers new perspectives on controlling memory.

Paper: “Hippocampal LTP and contextual learning require surface diffusion of AMPA receptors”
Reprinted from materials provided by CNRS.

“Time Is Motor Neuron: Therapeutic Window and Its Correlation with Pathogenetic Mechanisms in Spinal Muscular Atrophy” has been published in Molecular Neurobiology. This work was supported in part by JPND through the DAMNDPATHS project, selected under the 2013 call for cross-disease analysis of pathways related to neurodegenerative diseases.

Scientists have identified a toxic cascade that results in neuronal degeneration in people with Parkinson’s disease (PD) and have determined how to interrupt it, reports a study published in the journal Science.

Using an antioxidant to intervene early in the disease process may break the cycle of degeneration and improve the function of neurons in Parkinson’s, according to the study.

Using human neurons from Parkinson’s patients, the scientists identified a toxic cascade of mitochondrial and lysosomal dysfunction initiated by an accumulation of oxidized dopamine and a protein called alpha-synuclein. The study demonstrated that an accumulation of oxidized dopamine depressed the activity of lysosomal glucocerebrosidase (GCase), an enzyme implicated in PD. That depression in turn weakened overall lysosomal function and contributed to degeneration of neurons.

The accretion of oxidized dopamine didn’t just interfere with lysosomes, however. The scientists discovered that the dopamine also damaged the neurons’ mitochondria by increasing mitochondrial oxidant stress. These dysfunctional mitochondria led to increased oxidized dopamine levels, creating a vicious cycle.

After identifying the toxic cascade, the researchers looked for ways to disrupt it. They noted that by treating dopamine neurons with specific antioxidants early in the toxic cascade process attenuated or even prevented the downstream effects in human dopaminergic neurons. This approach may be a future therapy target. However, since neurodegeneration creates damage before symptoms are apparent, an antioxidant therapy may also require genetic testing and other screening measures such as brain imaging and other clinical signifiers to identify patients in the early stages of the disease.

Paper: “Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease”
Reprinted from materials provided by Northwestern University.