Author Archives: jpnd

A new study has uncovered a molecular mechanism in the prion protein, a protein responsible for neurodegenerative diseases, which may explain why nerve cells degenerate in these disorders. The findings appear in the journal eLife.

The prion protein plays a crucial role in fatal neurodegenerative disorders like Creutzfeldt-Jakob disease in humans and “mad cow disease” in cattle. Prion diseases are part of a larger group of human neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Huntington’s diseases, which are all due to the abnormal accumulation of protein aggregates in the brain.

Using a multi-disciplinary approach involving electrophysiological, cellular and biophysical techniques, the researchers found that parts of the prion protein produced abnormal electrical currents in cells. Antibodies that interfered with functioning did the same. Importantly, the antibody treatment also caused severe degeneration of nerve cell dendrites, the regions that are essential for normal communication between nerve cells. The researchers applied a sophisticated chemical technique to demonstrate that the two ends of the prion protein interact with each to alter the amount of toxic signal that is delivered.

As a result of their findings, the researchers caution against administering antibodies against the prion protein as a possible therapy for both prion and Alzheimer’s diseases.

Paper: “The N-terminus of the prion protein is a toxic effector regulated by the C-terminus”
Reprinted from materials provided by Boston University Medical Center.

New research shows that the APP gene variant protecting against Alzheimer’s disease significantly decreases plasma beta-amyloid levels in a population cohort. This is a significant discovery because many ongoing drug trials in the field of Alzheimer’s disease focus on decreasing beta-amyloid levels in the brain tissue. According to the study, a 30% life-long decrease in beta-amyloid levels is not associated with detrimental effects on lipid or glucose metabolism, or on any other metabolic factors.

The findings were published in Annals of Neurology.

Alzheimer’s disease is a neurodegenerative disease strongly characterised by the accumulation of beta-amyloid in the brain tissue. Uncovering the genetic pathogenesis of Alzheimer’s disease has been a target of great interest over the past few years, and genome-wide mapping studies focusing on risk genes have led to significant advances in the field. These studies have identified not only several new risk genes for Alzheimer’s disease, but also gene variants that protect against it.

Research groups focusing on Alzheimer’s disease and diabetes have now shown that the APP A673T gene variant, which is a variant in the amyloid precursor protein gene protecting against Alzheimer’s disease, leads to an average of 30 per cent decreased levels of the beta-amyloid subtypes 40 and 42. The effects of this previously discovered gene variant were analysed by utilising data from the unique and extensive METSIM study, which comprises 10,000 men living in the eastern part of Finland. Approximately 0.3% of the population are carriers of the APP A673T gene variant.

The findings on the role of the APP A673T gene variant in Alzheimer’s disease facilitate the planning of future research. This insight, in turn, could enable the identification of new drug targets, increasingly good predictive biomarkers and the development of personalised medical applications.

Paper: “Decreased plasma β-amyloid in the Alzheimer’s disease APP A673T variant carriers”
Reprinted from materials provided by University of Eastern Finland.

A team of researchers is using breakthrough gene-editing technology to develop a new screening tool for Parkinson’s disease. The technology allows scientists in the lab to “light up” and then monitor alpha-synuclein, a brain protein that has been associated with Parkinson’s. The study was published in Scientific Reports.

The researchers used CRISPR Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) gene-editing technology. The system is one of research’s fastest growing biomedical techniques that allows scientists to make specific changes in the DNA of plants and animals while not killing cells. The system is becoming instrumental in studying genetically based treatments for diseases including cancer and Parkinson’s.

Using the CRISPR technique, the team edited the alpha-synuclein gene and inserted a luminescent tag made from the same proteins that cause fireflies to light up. Every time the cell creates the alpha-synuclein protein, the tag gives off a light. The team found that measuring the light was a reliable method to measure alpha-synuclein production.

With the engineered cells, researchers can screen new and existing drugs to see how they regulate alpha-synuclein level in patients. The scientists hope to go on to identify ways to reduce alpha-synuclein production that can possibly prevent Parkinson’s or its progression in patients diagnosed with the disease.

Paper: “A novel tool for monitoring endogenous alpha-synuclein transcription by NanoLuciferase tag insertion at the 3′end using CRISPR-Cas9 genome editing technique”
Reprinted from materials provided by University of Central Florida.

A study has found that abnormal proteins found in Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease all share a similar ability to cause damage when they invade brain cells.

The finding potentially could explain the mechanism by which Alzheimer’s, Parkinson’s, Huntington’s, and other neurodegenerative diseases spread within the brain and disrupt normal brain functions. The study was published in Acta Neuropathologica.

Previous research has suggested that in all three diseases, proteins that are folded abnormally form clumps inside brain cells. These clumps spread from cell to cell, eventually leading to cell deaths. Different proteins are implicated in each disease: tau in Alzheimer’s, alpha-synuclein in Parkinson’s and huntingtin in Huntington’s disease.

The researchers focused on how these misfolded protein clumps invade a healthy brain cell. The authors observed that once proteins get inside the cell, they enter vesicles (small compartments that are encased in membranes). The proteins damage or rupture the vesicle membranes, allowing the proteins to then invade the cytoplasm and cause additional dysfunction.

The researchers said the finding that protein clumps associated with the three diseases cause the same type of vesicle damage was unexpected. The researchers, who are based in the U.S., initially focused on alpha-synuclein proteins associated with Parkinson’s disease. They asked a French collaborator known for his ability to generate distinct types of alpha-synuclein to send them different types. Without telling the researchers, the collaborator sent other types of proteins as well. This led to the surprise finding that tau and huntingtin proteins also can damage vesicles.

Paper: “Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins”
Reprinted from materials provided by Loyola University Health System.

A new study heightens concerns over the detrimental short- and long-term impact of airborne iron-rich strongly magnetic combustion-derived nanoparticles (CDNPs) present in dogs and young urbanites’ brains. Using transmission electron microscopy, the researchers documented by abundant combustion nanoparticles in neurons, glial cells, choroid plexus, and neurovascular units of Mexico City dogs, children, teens and young adults chronically exposed to concentrations above the US-EPA standards for fine particulate matter. These findings were published in the Journal of Alzheimer’s Disease.

The detrimental impact of these tiny particles getting into the brain through the nasal and olfactory epithelium, the lungs and the gastrointestinal system is quickly recognized by extensive alterations in critical neuronal organelles including mitochondria, as well as axons and dendrites. Since these nanoparticles are in close contact with neurofilaments, glial fibers and chromatin, the researchers are very concerned about their potential for altering microtubule dynamics, accumulation and aggregation of unfolded proteins, mitochondrial dysfunction, altered calcium homeostasis and insulin signaling, and epigenetic changes.

These particles are ubiquitous and present in high concentrations in children as young as 3 years old. The particles contain transition neurotoxic metals and they are causing extensive brain damage in key organelles. It is now necessary to explore the potential impact of these particles in brain neurodegeneration.

Paper: “Combustion-Derived Nanoparticles in Key Brain Target Cells and Organelles in Young Urbanites: Culprit Hidden in Plain Sight in Alzheimer’s Disease Development”
Reprinted from materials provided by IOS Press.

The development of Parkinson’s disease is linked to an overabundance of the protein alpha-synuclein, which is found mainly at the end of neurons in what is called the nerve terminal. Since the link was first discovered in the 1990s, researchers have been working to precisely identify its role in Parkinson’s disease.

Now scientists have found that alpha-synuclein hinders a key step involved in the transmission of neuronal signals, which is essential for higher-brain functioning: vesicle endocytosis at the nerve terminal.

The study was published in the Journal of Neuroscience.

Neurotransmission is a process that allows neurons to pass signals between one another — signals important for motor, sensory, and cognitive functioning. When an electrical signal arrives at a nerve terminal and needs to be passed along to the next neuron, neurotransmitters packed in vesicles mediate this process. After being released, the neurotransmitter is caught by receptors in an adjacent neuron and the signal is passed along for further transmission. Meanwhile, the empty vesicle is recycled back into the nerve terminal to be used again.

The retrieval of an emptied vesicle membrane is called “endocytosis,” and it is this process that an overabundance of alpha-synuclein disrupts. Endocytosis is critical for proper neurotransmission — when it is inhibited, the rest of the steps involved in transmission are affected as well.

High-frequency transmission, in which vesicles are heavily used, is important for processes such as sensory perception, generating memories, and motor control. The researchers found that when endocytosis is inhibited, high-frequency transmission breaks down much more quickly than it would under normal circumstances.

A deeper look into the mechanism by which alpha-synuclein inhibits endocytosis revealed toxic effects of the over-assembly of microtubules. Too much alpha-synuclein in the nerve terminal causes microtubules to over-assemble and somehow get in the way of endocytosis.

Researchers believe that this inhibitory process caused by an overabundance of alpha-synuclein is what occurs in the early stages of Parkinson’s disease, before morphological changes such as the loss of function and death of neurons begins.

Paper: “Wild-type monomeric α-synuclein can impair vesicle endocytosis and synaptic fidelity via tubulin polymerization at the calyx of Held”
Reprinted from materials provided by Okinawa Institute of Science and Technology Graduate University – OIST.

A phase 2 clinical trial in young adults with Down syndrome of a drug being investigated for the treatment of Alzheimer’s disease supports further investigation of its potential, according to the researchers behind the four-week trial of scyllo-inositol, also known as ELND005. The results have been published in the Journal of Alzheimer’s Disease.

The most common form of intellectual disability in the United States, Down syndrome is caused by an extra copy of chromosome 21. People with Down syndrome exhibit various degrees of intellectual disability and are at greatly increased risk of developing Alzheimer’s dementia as they age. Excess activity of the genes on chromosome 21 — including the gene for the amyloid precursor protein, the source of amyloid plaques found in the brains of people with Alzheimer’s disease — is thought to play a role in the cognitive challenges of people with Down syndrome.

Another chromosome 21 gene believed to play a role in Down syndrome contributes to the metabolism of myo-inositol, a signaling molecule increased in the brains of children and adults with Down syndrome at levels that correlate to the severity of symptoms. Lifelong exposure to increased levels of both amyloid and myo-inositol are believed to contribute to brain dysfunction and cognitive disability. Scyllo-inositol may have potential to improve cognition in patients with Down syndrome both by decreasing amyloid levels and regulating myo-inositol-dependent signaling in the brain.

The clinical trial enrolled 23 adults with Down syndrome, ages 18 to 45, who were randomised to receive one of two dosages of scyllo-inositol — 250 mg either daily or twice a day — or a placebo. All but one participant completed the four-week trial with no significant deviations from the protocol. There were no serious adverse events and no changes in vital signs, laboratory tests or other physical findings. While treatment produced no apparent cognitive or behavioral changes, the duration of the trial was too short to capture such effects.