Tag Archives: animal models

Scientists have solved a longstanding problem with modeling Parkinson’s disease in animals. Using newfound insights, they improve both cell and animal models for the disease, which can propel research and drug development.

Parkinson’s disease is characterized by the appearance of protein clumps within neurons in the brain, called Lewy bodies. Reproducing Lewy bodies in animals in order to model the disease for research and drug screening has proven notoriously difficult, leaving a gap in Parkinson’s research and treatment. Scientists have now shown where the discrepancy between humans and animals lies. Using the knowledge, the scientists have produced cellular and mouse models that reproduce the evolution of Parkinson’s disease more accurately for both fundamental research and drug development. The work is published in PNAS.

In humans, Lewy bodies form when the brain produces twice the normal amount of alpha-synuclein. When mice, which are often used to model human diseases, are used to model Parkinson’s, they are genetically engineered to overproduce it. But human alpha-synuclein does not form fibrils and Lewy bodies when produced in mice.

Mice produce three types of their own synuclein, which are similar to human alpha-synuclein. Because of this, they are referred to as its “homologues”. The researchers found that human alpha-synuclein does not form Lewy bodies in mice because its homologues in the animal prevent it from doing so. This discovery explains why it is so difficult to model Parkinson’s disease in normal mice, which have all of their synuclein homologues. In other words, the key to successfully modeling the disease in mice is to genetically suppress their homologues of human alpha-synuclein.

Working off their genetically engineered mice and neuronal cultures, the team developed and characterized new models for Lewy bodies for the scientific and medical community. Hilal Lashuel expects that the new insights will advance the development of neuronal and in vivo models that reproduce features of Parkinson’s disease, and allow screening for new drugs. “We now have a very well-characterized model that offers a powerful tool for rapid screening of molecular pathways involved in Parkinson’s disease,” he says.

Source: École polytechnique fédérale de Lausanne

A study conducted on mice offers a new type of immunotherapy approach for treating Alzheimer’s disease. This involves amplifying a specific population of T lymphocytes that regulate immune and neuroinflammatory mechanisms that develop during the disease.

These results are published in the journal Brain.

In recent years, a body of substantive work has enabled the start of gaining further insight into complex immune and neuroinflammatory mechanisms associated with Alzheimer’s disease. The researchers offer further proof of concept on the efficacy of innovative immunotherapy strategy in mice that is based on an immunomodulation approach.

Researchers have shown, in earlier work with mice, that a specific population of T lymphocytes, known as T regulators (or Treg), modulated specific Ab peptide T lymphocytes that accumulate in the brains of sick people. Researchers chose to evaluate the effect of Treg cells on disease progression using a mouse model.

To do this, they either depleted or amplified Treg cells at the early stage of the disease. They found that a Treg deficiency accelerated the onset of cognitive disorders and was associated with a decrease in the presence of microglial cells in deposits of Ab peptide.

By contrast, prolonged Treg amplification using low doses of interleukin-2 injected intraperitoneally increases the microglial cell response and delays the onset of memory impairment.

This immunomodulation approach involving the injection of low doses of interleukin-2, already tested in some bone marrow transplant clinical protocols and for type 1 diabetes, now seems to be a new therapeutic strategy for Alzheimer’s disease. Researchers are already planning a pilot clinical trial in humans and are also considering the possibility of modulating some specific sub-populations of T lymphocytes to refine the response.

Source: Inserm

Researchers have discovered that an existing compound, previously tested for diabetes, offers hope for slowing Huntington’s Disease (HD) and its symptoms.

The study was published in Nature Medicine.

“We’re very excited by our pre-clinical testing of this compound (KD3010),” said Albert La Spada, MD, PhD, professor of pediatrics, cellular and molecular medicine and neurosciences at UC San Diego School of Medicine. “It improved motor function, reduced neurodegeneration and increased survival in a mouse model of Huntington’s disease and reduced toxicity in neurons generated from human HD stem cells.”

The discovery of the drug’s potential in HD builds upon more than a decade of research into the disorder’s underlying molecular pathology. Much of that work has centered on misfolded proteins, which are known to be key culprits in HD and several other neurodegenerative diseases.

At the cellular level, the drug improved mitochondrial energy production and helped mice get rid of the misfolded proteins. Since misfolded proteins also underlie Alzheimer’s, Parkinson’s and other neurodegenerative disorders, researchers hope that, if successful in HD, the compound can also be tested in other related neurological diseases.

Source: UC San Diego

Alzheimer’s patients frequently suffer from sleep disorders, mostly even before they become forgetful, and it is known that sleep plays a very important role in memory formation. Researchers have now been able to show for the first time how the pathological changes in the brain act on the information-storing processes during sleep. Using animal models, they were able to decode the exact mechanism and alleviate the impairment with medicinal agents. The study was published in Nature Neuroscience.

The sleep slow waves, also known as slow oscillations, which our brain generates at night, have a particular role in consolidating what we have learned and in shifting memories into long-term storage. These waves are formed via a network of nerve cells in the brain’s cortex, and then spread out into other parts of the brain, such as the hippocampus.

The study used mouse models, which form the same protein deposits, known as β-amyloid plaques, that are visible in human patients. The scientists were able to show that these plaques directly impair the slow wave activity. The scientists also succeeded in decoding this defect at the molecular level: correct spread of the waves requires a precise balance to be maintained between the excitation and inhibition of nerve cells. In the Alzheimer models, this balance was disturbed by the protein deposits, so that inhibition was reduced.

The researchers used this knowledge to treat the defect with medication. One group of sleep-inducing drugs, benzodiazepines, is known to boost inhibitory influences in the brain. If the scientists gave small amounts of this sleep medication to the mice (approximately one-tenth of the standard dose), the sleep slow waves were able to spread out correctly again. In subsequent behavioral experiments, they were able to demonstrate that learning performance had improved as well.

Source: Technical University of Munich