Discovery presents treatment hope for Alzheimer’s and other neurodegenerative diseases

There is new hope for the treatment of Alzheimer’s and other neurological diseases following a ground-breaking discovery made by an Australian-Chinese research collaboration.

Researchers from the University of South Australia and the Third Military Medical University in China have discovered a signal pathway within cells, and also invented a potential drug that could stop degeneration and actually improve learning and memory in affected patients.

UniSA’s Professor Xin-Fu Zhou and colleagues have been investigating tauopathies — which refers to a class of diseases caused by misfolding of the tau protein inside nerve cells that results in cell damage and eventually cell death.

These diseases include Alzheimer’s, Parkinson’s and Motor Neuron Disease, all of which presently have no cure.

Specifically, the team has looked into frontotemporal lobe degeneration (FTLD), a term representing a group of clinical syndromes related to cognitive impairment, behavioural abnormalities and speech disorders.

Professor Zhou says that previously it was unknown how the gene mutation was responsible for causing cell death or damage — referred to generally as neurodegeneration, and dementia in patients with FTLD and other motor neuron diseases. “Right now there is no treatment available at all,” Prof Zhou says. “We have been investigating how these tauopathies (diseases) have some common pathology, including a particular tau protein that plays a critical role in nerve cell function.”

Tau protein is a protein that stabilises microtubules and it is specifically abundant in neurons of the nervous system, but not in elsewhere.

“Our research found that in both the animal model and human brains, the signal of neurotrophins and receptors is abnormal in brains with FTLD,” Prof Zhou says.

“We discovered an increase in the neurotrophin signalling pathway that is related to life and death of nerve cells, known as proNGF/p75, and then found blocking its functions was shown to reduce cell damage.

“Thus, in this paper we not only discovered a signaling pathway but also invented a potential drug for treatment of such diseases.”

Given this strong evidence now available, the next stage is a clinical trial and South Australian biotech company Tiantai Medical Technology Pty Ltd has recently acquired a licence to further develop and commercialise this medical technology.

Professor Zhou says this industry involvement means there is an opportunity to translate the discovery into a treatment of Alzheimer’s disease and other tauopathies.

The paper published in Molecular Psychiatry is a collaborative work between two laboratories led by Professor Xin-Fu Zhou, University of South Australia and Professor Yanjiang Wang, the Third Military Medical University.

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Alzheimer’s disease and type 2 diabetes: Hope for inhibitors against amyloid plaques: Designed peptides as potential inhibitors of amyloid plaques

Effective therapeutics to counteract the formation of amyloid plaques in Alzheimer’s disease and type 2 diabetes are not yet available. Scientists at the Technical University of Munich (TUM) have now come a little bit closer to a solution: They have described a new class of designed macrocyclic peptides that are highly potent inhibitors of amyloid formation.

Amyloid plaques, which are protein deposits, play a crucial role in the development of Alzheimer’s disease and type 2 diabetes. Several teams of scientists around the world are working on finding ways to prevent amyloid plaque formation in the human brain.

The research team of Aphrodite Kapurniotu, Professor for Peptide Biochemistry (TUM) has been working on an idea for some time now in collaboration with the teams of Professor Martin Zacharias (TUM), Professor Gerhard Rammes (TUM Rechts der Isar Hospital) and Professor Jürgen Bernhagen (Institute for Stroke and Dementia Research (ISD) at Ludwig Maximilian University (LMU)). The researchers present now macrocyclic peptides (MCIPs) as potent inhibitors of amyloid formation; they reported their results in the journal Angewandte Chemie. The work has been supported by Deutsche Forschungsgemeinschaft (DFG) collaborative research center SFB 1035.

New class of amyloid inhibitors

In its new study, the team presents macrocyclic peptides, developed as a new class of amyloid inhibitors. “We have discovered an MCIP that is stable in human blood plasma and can also overcome the human blood-brain barrier in an in vitro cell culture model,” explains Professor Kapurniotu. She adds: “So far we were ‘only’ able to demonstrate these properties in the test tube — thus further research is necessary. But these are two highly desirable properties for inhibitors of Alzheimer’s amyloid.”

TUM has already applied for a patent for the newly developed macrocyclic peptides. “They could be a good alternative to the currently pursued antibody-based approaches as therapeutics against Alzheimer’s amyloid plaque formation because they are easy to produce, have promising properties and, due to their peptidic nature, they will be significantly cheaper than antibodies,” says Professor Kapurniotu.

“Therefore, further investigations are now planned to verify whether the MCIPs are also effective in in vivo models. Furthermore, the MCIPs could also be suitable as templates for the development of small molecule peptidomimetics (molecules mimicking peptide chains), which might also find application as anti-amyloid drugs in Alzheimer’s and type 2 diabetes.

The research work was funded by the German Research Foundation (DFG) within the SFB 1035.

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Brain iron levels may predict multiple sclerosis disabilities

A new, highly accurate MRI technique can monitor iron levels in the brains of multiple sclerosis (MS) patients and help identify those at a higher risk for developing physical disability, according to a study published in the journal Radiology.

MS is a disease that attacks three critical components of the central nervous system: the neurons (nerve fibers), myelin (the protective sheath around the neurons), and the cells that produce myelin. Common symptoms of MS include weakness, spasticity and pain. The disease can progress in many patients, leaving them severely disabled. Brain atrophy is the current gold standard for predicting cognitive and physical decline in MS, but it has limitations, said study lead author Robert Zivadinov, M.D., Ph.D., professor of neurology at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo (UB) in Buffalo, N.Y. He is director of the Buffalo Neuroimaging Analysis Center in the Jacobs School and the Center for Biomedical Imaging at UB’s Clinical and Translational Science Institute.

“Brain atrophy takes a long time to see,” he said. “We need an earlier measure of who will develop MS-related disability.”

MRI studies of iron concentration have emerged recently as a promising measure of changes in the brain associated with MS progression. Iron is vital for various cellular functions in the brain, including myelination of neurons, and both iron overload and iron deficiencies can be harmful.

“It is known that there is more iron in the deep gray matter structures in MS patients, but also we’ve seen in recent literature that there are regions where we find less iron in the brains of these patients,” Dr. Zivadinov said.

Dr. Zivadinov and colleagues recently compared brain iron levels in people with MS to those of a healthy control group using an advanced MRI technique called quantitative susceptibility mapping. A brain region with more iron would have higher magnetic susceptibility, and one with less iron would have lower susceptibility.

The researchers performed the mapping technique on 600 MS patients, including 452 with early-stage disease and 148 whose disease had progressed.

Compared to 250 healthy control participants, MS patients had higher levels of iron in the basal ganglia, a group of structures deep in the brain that are central to movement. However, the MS patients had lower levels of iron in their thalamus, an important brain region that helps process sensory input by acting as a relay between certain brain structures and the spinal cord. The lower iron content in the thalamus and higher iron content in other deep gray matter structures of people with MS were associated with longer disease duration, higher disability degree and disease progression.

This association with clinical disability persisted even after adjusting for changes in the brain volumes of each individual structure.

“In this large cohort of MS patients and healthy controls, we have reported, for the first time, iron increasing in the basal ganglia but decreasing in thalamic structures,” Dr. Zivadinov said. “Iron depletion or increase in several structures of the brain is an independent predictor of disability related to MS.”

The results point to a potential role for quantitative susceptibility mapping in clinical trials of promising new drugs, Dr. Zivadinov said. Current treatments involving anti-inflammatory drugs do not prevent MS patients from developing disability.

“Susceptibility is an interesting imaging marker of disease severity that can predict which patients are at severe risk of progressing,” Dr. Zivadinov said. “To be able to act against changes in susceptibility would be extremely beneficial.”

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