Yearly Archives: 2017

Scientists have published a proof-of-concept study in the journal Neurobiology of Disease demonstrating that an antidepressant drug which has been on the market for more than 50 years could slow the progression of Parkinson’s.

The drug nortriptyline, which has been used to treat depression and nerve pain, stopped the growth of abnormal proteins that can build up in the brain and lead to the development of the disease.

Researchers began by examining previous patient data to see if individuals who were on antidepressants started a standard Parkinson’s therapy called levodopa later than those not taking the antidepressant. Levodopa increases levels of dopamine, a natural chemical in the body that sends signals to other nerve cells, which is usually significantly decreased in people with Parkinson’s. The medication also alleviates symptoms of the disease such as tremors and poor muscle control.

The researchers observed that people on tricyclic antidepressants did not need levodopa until much later, compared to patients not taking a tricyclic for depression.

Researchers then began testing rats with the tricyclic antidepressant nortriptyline and observed that it decreased the amount of alpha-synuclein, an abnormal protein that can build up in the brain and cause nerve cells to die. Alpha-synuclein buildup is a hallmark of Parkinson’s diease.

Finally, the scientists added nortriptyline to alpha-synuclein proteins in a test tube model and observed that the addition of the antidepressant caused the proteins to move and change shape more rapidly, preventing them from clumping together.

To further back up his research, he enlisted the help of his colleague and co-author Lisa Lapidus, who in previous studies had already detected whether certain compounds could bind to alpha-synuclein and stop it from accumulating.

Understanding how these proteins can clump together could point researchers in new directions and help them find other possible drugs that could potentially treat Parkinson’s. One such new drug that can affect both Parkinsons, depression, and anxiety is CBD, which Daily CBD has a list of working products you can learn more about.

Paper: “Nortriptyline inhibits aggregation and neurotoxicity of alpha-synuclein by enhancing reconfiguration of the monomeric form”

Reprinted from materials provided by Michigan State University.

The protein amyloid beta is believed to be a major cause of Alzheimer’s disease. BACE inhibitors, which reduce the production of amyloid beta are therefore promising candidates for new drug treatments. A research team has recently demonstrated that one such BACE inhibitor reduces the amount of amyloid beta in the brain, restoring the normal function of nerve cells and improving memory performance. The team’s findings were published in the journal PNAS.

Using a mouse model of Alzheimer’s, the researchers tested a substance that inhibits beta secretase. In mice, as in humans, the disease causes amyloid beta plaques in the brain, which cause memory loss. In the study, mice were examined after having received the inhibitor in their food for up to eight weeks. Researchers observed individual nerve cells in the brain using an imaging technique called two-photon microscopy.

After the course of treatment, the mice had less amyloid beta in their brain, an unsurprising finding as its production was inhibited. However, their brain functions also normalised, with fewer hyperactive nerve cells and slow-wave brain patterns that were similar to those in healthy mice. Researchers also observed that the animals’ memory improved, with the treated mice finding a hidden platform in a water-filled maze as quickly as their healthy counterparts.

The scientists’ findings will soon find its way into clinical practice: a large-scale clinical trial is planned with around 1000 participants to test a slightly modified form of the BACE inhibitor.

Paper:“BACE inhibition-dependent repair of Alzheimer’s pathophysiology”

Reprinted from materials provided by TUM.

While memory and learning as people age have been intensively studied, changes in how people map their surroundings and construct and follow directions are not well understood.  Now a review published in the journal Neuron discusses the possibility that age-related declines in navigational ability could contribute to tools for the early diagnosis of Alzheimer’s disease.

Today, Alzheimer’s disease is diagnosed using factors such as medical history, genetic risk factors and performance on tests that measure memory, language and reasoning impairments. However the research team suggests that navigational impairments are among the earliest signs of the Alzheimer’s progression. According to the scientists, abnormal results on standard cognitive tests may only show up 10 years after the onset of Alzheimer’s. A navigation-based diagnostic test could reduce that window.

Navigational testing is held back by the lack of standard tests for navigational tasks and population norms with which to evaluate results. Now, more-affordable and portable virtual reality technology means it is possible to develop standardised tests. The second challenge is that navigational abilities vary greatly between individuals, meaning an effective diagnostic tool would need to track an individual’s navigational capabilities over the course of their life to identify signs of early or accelerated decline.

With such data and the improved virtual reality setups, the researchers conclude that a navigational test battery analogous to those used for memory and learning will be feasible.

Paper: “The Aging Navigational System”.

Reprinted from materials provided by Cell Press.

A gene called ” triggering receptor expressed on myeloid cells 2”, or TREM2, has been associated with a variety of neurodegenerative diseases, such as Alzheimer’s disease, Frontotemporal lobar degeneration, Parkinson’s disease, and Nasu-Hakola disease. Recently, a rare mutation in the gene has been shown to increase the risk for developing Alzheimer’s disease.

Independently from each other, two research groups have now revealed the molecular mechanism behind this mutation. Their research, published in EMBO Molecular Medicine, sheds light on the role of TREM2 in normal brain function and suggests a new therapeutic target in Alzheimer’s disease treatment.

Alzheimer’s disease, like other neurodegenerative diseases, is characterized by the accumulation of specific protein aggregates in the brain. Specialized brain immune cells called microglia strive to counter this process by engulfing the toxic buildup. But as the brain ages, microglia eventually fail to eliminate all the damaging material.

TREM2 is active on microglia and enables them to carry out their protective function. The protein spans the microglia cell membrane and uses its external region to detect dying cells or lipids associated with toxic protein aggregates. Subsequently, TREM2 is cut in two. The external part is shed from the protein and released, while the remaining part still present in the cell membrane is degraded. To better understand TREM2 function, the two research groups took a closer look at its cleavage.

Using different approaches, both groups first determined the exact site of protein shedding and found it to be at amino acid 157. Amino acid 157 was recently found to be the position of a mutation which increases the risk of Alzheimer’s disease. These observations indicate that protein cleavage is perturbed in the p.H157 mutant and that this alteration promotes disease development.

Next, each group investigated the biochemical properties of the p.H157Y mutant protein more closely. They found that the mutant was cleaved more rapidly than a healthy version of the protein.

While most TREM2 mutations affect protein production, the mechanism behind p.H157Y is somewhat different. The p.H157Y mutation allows the protein to be correctly manufactured and transported to the microglia cell surface, but then it is cleaved too quickly. As a result, there is too little full-length TREM protein on microglia, which suggests that stabilising TREM2 to make it less susceptible to cleavage may be a viable therapeutic strategy.

Papers: “TREM2 shedding by cleavage at the H157‐S158 bond is accelerated for the Alzheimer’s disease‐associated H157Y variant” and “An Alzheimer‐associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function”

Reprinted from materials provided by EMBO.