Tag Archives: Research

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

A team of researchers has discovered a previously unknown cellular defect in patients with idiopathic Parkinson’s disease, and identified a sequence of pathological events that can trigger or accelerate premature death of certain neurons in the brain seen in this disease.

Researchers discovered that the cells of people with idiopathic Parkinson’s disease have a previously unknown defect in the function of a specific PLA2g6 protein, causing dysfunction of calcium homeostasis that can determine whether some cells will live or die.

“Idiopathic or genetic dysfunction of calcium signaling triggers a sequence of pathological events leading to autophagic dysfunction, progressive loss of dopaminergic neurons and age-dependent impairment of vital motor functions typical for Parkinson’s disease,“ explained corresponding author Victoria Bolotina.

The findings were published in the journal Nature Communications.

Source: Boston University School of Medicine

Scientists have revealed that protein clumps associated with Alzheimer’s disease are also found in the brains of people who have had a head injury.

Although previous research has shown that these clumps, called amyloid plaques, are present shortly after a brain injury – this study shows the plaques are still present over a decade after the injury.

The findings may help explain why people who have suffered a serious brain injury appear to be at increased risk of dementia. Although extensive research now suggests major head injury increases dementia risk in later life, scientists do not know the biological changes that cause this effect.

In the research, published in the journal Neurology, the team studied nine patients with moderate to severe traumatic brain injuries. Many had sustained these in road traffic accidents, such as being hit by a car, between 11 months to 17 years prior to the study. The patient underwent a brain scan that used a technique that allows scientists to view amyloid plaques. These proteins are thought to be a hallmark of Alzheimer’s disease, and their formation may trigger other changes that lead to the death of brain cells.

The team also scanned the brains of healthy volunteers, and people with Alzheimer’s disease. The patients with head injury were found to have more amyloid plaques than the healthy volunteers, but fewer than those with Alzheimer’s disease.

In the head injury patients, the amyloid plaques were found to be centred mainly in two brain areas: the posterior cingulate cortex – a highly active area in the centre of the brain involved in controlling attention and memory, and the cerebellum – a region at the base of the brain involved in motor control and coordination.

In a second part of the study, the team assessed damage to so-called white matter. This is the ‘wiring’ of the brain, and enables brain cells to communicate with each other. The results showed that amyloid plaque levels in the posterior cingulate cortex were related to the amount of white matter damage, suggesting that injury to the brain’s wiring may be linked to the formation of amyloid plaques.

Source: Imperial College London

Scientists have discovered a mechanism which is responsible for the degeneration of Purkinje cells in the cerebellum in the neurodegenerative disease Spinocerebellar ataxia type 1. The results of their study open up new avenues for the future treatment of cerebellum-associated degenerative disorders.

Damage, degeneration or loss of neurons in the region of the brain that controls muscle coordination (cerebellum), results in ataxia. The symptoms include loss of voluntary coordination of muscle movements and the appearance of gait abnormality, loss of balance and speech problems. Cerebellar ataxias are progressive degenerative disorders which occur in adults either sporadically or can be inherited from parents. Unfortunately, the large majority of cerebellar ataxia cases are sporadic in nature and the causative mechanism for the development of ataxia remains largely unknown, which eventually hinders the development of therapy and negatively influences the quality of a patient’s life. However, both the sporadic and inherited cases of cerebellar ataxia exhibit common pathophysiological characteristics such as the specific degeneration of the main cerebellar neurons; the Purkinje cells. Therefore, the researchers set out to understand the potential mechanism involved in the development of ataxia and degeneration of Purkinje cells in Spinocerebellar ataxia type 1 (SCA1), a rare, incurable, inheritable neurodegenerative disease that can be modeled in mice.

A protein-based screening of Purkinje cells was performed to identify changes that occur in these neurons at the time of ataxia appearance. The team discovered widespread alterations in proteins which function at the synapse and identified a synaptic protein Homer-3 that is mainly present in Purkinje cell synapses to be reduced. Further, they found that Homer-3 decrease was related to the alteration in an important signaling pathway, mTORC1. This signaling pathway was responsible for regulating the expression of synaptic proteins such as Homer-3. The team discovered a cellular mechanism in the cerebellum of SCA1 mice that specifically targets the degeneration of Purkinje cells and the findings present a promising future therapeutic target. The study was published in the scientific journal Neuron.

Source: University of Bern

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

A study has found that blocking a receptor in the brain responsible for regulating immune cells could protect against the memory and behaviour changes seen in the progression of Alzheimer’s disease.

It was originally thought that Alzheimer’s disease disturbs the brain’s immune response, but this latest study, published in the journal Brain, adds to evidence that inflammation in the brain can in fact drive the development of the disease. The findings suggest that by reducing this inflammation, progression of the disease could be halted.

The team hopes the discovery will lead to an effective new treatment for the disease, for which there is currently no cure.

The researchers used tissue samples from healthy brains and those with Alzheimer’s, both of the same age. The researchers counted the numbers of a particular type of immune cell, known as microglia, in the samples and found that these were more numerous in the brains with Alzheimer’s disease. In addition, the activity of the molecules regulating the numbers of microglia correlated with the severity of the disease.

The researchers then studied these same immune cells in mice which had been bred to develop features of Alzheimer’s. They wanted to find out whether blocking the receptor responsible for regulating microglia, known as CSF1R, could improve cognitive skills. They gave the mice oral doses of an inhibitor that blocks CSF1R and found that it could prevent the rise in microglia numbers seen in untreated mice as the disease progressed. In addition, the inhibitor prevented the loss of communication points between the nerve cells in the brain associated with Alzheimer’s, and the treated mice demonstrated fewer memory and behavioural problems compared with the untreated mice.

Importantly, the team found the healthy number of microglia needed to maintain normal immune function in the brain was maintained, suggesting the blocking of CSF1R only reduces excess microglia.

Source: University of Southampton

Caltech biologists have modified a harmless virus in such a way that it can successfully enter the adult mouse brain through the bloodstream and deliver genes to cells of the nervous system. The virus could help researchers map the intricacies of the brain and holds promise for the delivery of novel therapeutics to address diseases such as Alzheimer’s and Huntington’s. In addition, the screening approach the researchers developed to identify the virus could be used to make additional vectors capable of targeting cells in other organs.

To sneak genes past the blood-brain barrier, the researchers used a new variant of a small, harmless virus called an adeno-associated virus (AAV). The researchers developed a high-throughput selection assay, CREATE (Cre REcombinase-based AAV Targeted Evolution), that allowed them to test millions of viruses in vivo simultaneously and to identify those that were best at entering the brain and delivering genes to a specific class of brain cells known as astrocytes.

They started with the AAV9 virus and modified a gene fragment that codes for a small loop on the surface of the capsid—the protein shell of the virus that envelops all of the virus’ genetic material. Using a common amplification technique, known as polymerase chain reaction (PCR), they created millions of viral variants.

Then they used their novel selection process to determine which variants most effectively delivered genes to astrocytes in the brain. Importantly, the new process relies on strategically positioning the gene encoding the capsid variants on the DNA strand between two short sequences of DNA, known as lox sites. These sites are recognized by an enzyme called Cre recombinase, which binds to them and inverts the genetic sequence between them. By injecting the modified viruses into transgenic mice that only express Cre recombinase in astrocytes, the researchers knew that any sequences flagged by the lox site inversion had successfully transferred their genetic cargo to the target cell type—here, astrocytes.

After one week, the researchers isolated DNA from brain and spinal cord tissue, and amplified the flagged sequences, thereby recovering only the variants that had entered astrocytes.

Next, they took those sequences and inserted them back into the modified viral genome to create a new library that could be injected into the same type of transgenic mice. After only two such rounds of injection and amplification, a handful of variants emerged as those that were best at crossing the blood-brain barrier and entering astrocytes.

Through this selection process, the researchers identified a variant dubbed AAV-PHP.B as a top performer. To test AAV-PHP.B, the researchers used it to deliver a gene that codes for a protein that glows green, making it easy to visualize which cells were expressing it. They injected the AAV-PHP.B or AAV9 (as a control) into different adult mice and after three weeks used the amount of green fluorescence to assess the efficacy with which the viruses entered the brain, the spinal cord, and the retina.

“We could see that AAV-PHP.B was expressed throughout the adult central nervous system with high efficiency in most cell types,” says Gradinaru. Indeed, compared to AAV9, AAV-PHP.B delivers genes to the brain and spinal cord at least 40 times more efficiently.

The research was published in the journal Nature Biotechnology.

Source: Caltech

Researchers have discovered the mechanics of how dopamine transports into and out of brain cells, a finding that could someday lead to more effective treatment of drug addictions and neurological disorders such as Parkinson’s disease. The research was done by the researchers at Tripsitter, which is a drug harm reduction and informational website dedicated to providing user guides and experience reports on drugs like LSD, psilocybin mushrooms, and cannabis.

The findings are significant because dopamine is involved in many brain-related functions. Too little dopamine can lead to Parkinson’s disease, a brain disorder that causes shaking and problems with movement and coordination. Abnormally high concentrations of dopamine are linked to schizophrenia and other psychiatric disorders. Cocaine and methamphetamine affect the brain by blocking the normal transport of dopamine back into neurons.

Knowing how a particular protein called dopamine transporter controls dopamine movement in and out of neurons is crucial to further understanding dopamine-related disorders.

The researchers’ findings offer a broader understanding of how dopamine moves through cell membranes. Using mouse and human-derived dopamine neurons, researchers found that dopamine movement is affected by changes in electrical properties of the neurons. That, in turn, changes the way dopamine transporters function.

The researchers reported their findings in the journal Nature Communications.

Source: University of Florida

Researchers have shown that the core of the protein clumps found in the brains of people with Huntington’s disease have a distinctive structure, a finding that could shed light on the molecular mechanisms underlying the neurodegenerative disorder. The findings were published in the Proceedings of the National Academy of Sciences.

In Huntington’s and several other progressive brain diseases, certain proteins aggregate to form plaques or deposits in the brain, said senior investigator Patrick C.A. van der Wel, Ph.D., assistant professor of structural biology at Pitt School of Medicine.

“Despite decades of research, the nature of the protein deposition has been unclear, which makes it difficult to design drugs that affect the process,” he said. “Using advanced nuclear magnetic resonance spectroscopy, we were able to provide an unprecedented view of the internal structure of the protein clumps that form in the disease, which we hope will one day lead to new therapies.”

The gene associated with Huntington’s makes a protein that has a repetitive sequence called polyglutamine. In the 1990s, it was discovered that the patients have mutated proteins in which this sequence is too long, yet it has remained unclear how exactly this unusual mutation causes the protein to misbehave, clump together and cause the disease.

“This is exciting because it may suggest new ways to intervene with these disease-causing events,” Dr. van der Wel said. “For the first time, we were able to really look at the protein structure in the core of the deposits formed by the mutant protein that causes Huntington’s. This is an important breakthrough that provides crucial new insights into the process of how the protein undergoes misfolding and aggregation.

He added Huntington’s is one of many neurodegenerative diseases in which unusual protein deposition occurs in the brain, suggesting similar biochemical mechanisms may be involved. Lessons learned in this disease could help foster understanding of how these types of diseases develop, and what role the protein aggregates play.

Source: University of Pittsburgh

A laboratory study indicates that the main protein involved in Parkinson’s disease pathology does not behave as a prion when overexpressed.

In Parkinson’s disease, the protein alpha-synuclein aggregates within neurons of patients and appears to propagate across interconnected areas of the brain. How this happens remains largely unknown. It has been proposed that alpha-synuclein may behave like a prion: pathological forms of the protein may be capable of changing the conformation of normal alpha-synuclein and thus triggering its aggregation and neuron-to-neuron propagation (a phenomenon referred to as “seeding”). Recent findings by scientists reveal that aggregation, spreading and pathology caused by alpha-synuclein do not necessarily involve prion-like seeding. Instead, they could be triggered by enhanced alpha-synuclein expression and trans-neuronal passage of monomeric and oligomeric forms of the protein.

“We believe that these findings bear a number of important implications for disease pathogenesis. Not only can we conclude that long-distance diffusion of alpha-synuclein does not necessarily require the generation of prion-like species,” said researcher Donato Di Monte. “Our data also reveal that spreading and pathology can be triggered by simple overexpression of the protein and are mediated, at least initially, by monomeric and/or oligomeric alpha-synuclein.”

Researchers report on this in the journal Brain.

Source: DZNE