Category Archives: Research News (General)

Researchers have found a potentially promising treatment for Alzheimer’s disease, by noticing a similarity in the way insulin signaling works in the brain and in the pancreas of diabetic patients.

“In the pancreas, the Kir6.2 channel blockade increases the insulin signaling, and insulin signaling decreases the blood glucose levels,” says Dr. Shigeki Moriguchi, one of the authors of the paper. “In the brain, insulin signaling increases the acquisition of memory through CaM kinase II activation by Kir6.2 channel blockade.”

The research group concluded that Alzheimer’s disease can be described as a ‘diabetic disorder’ of the brain.

Memantine, a drug widely used to treat Alzheimer’s disease, is a well-known inhibitor of the N-methyl-D-aspartate (NMDA) receptors that prevent excessive glutamate transmission in the brain. Researchers have now found that memantine also inhibits the ATP-sensitive potassium channel (Kir6.2 channel), improving insulin signal dysfunction in the brain.

In their experiment with mice, the researchers found that memantine treatment improved impaired hippocampal long-term potentiation (LTP) and memory-related behaviors in the mice through the inhibition of KATP channel Kir6.2.

The researchers say they hope the results of their study and the parallels drawn with diabetes will lead to new treatments for Alzheimer’s disease using the inhibition of Kir6.2 channel.

Paper: “Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer’s disease therapy”
Reprinted from materials provided by Tohoku University.

New research reveals that foods like fruits and vegetables that are high in antioxidant nutrients and carotenoids are associated with better function in amyotrophic lateral sclerosis (ALS) patients around the time of diagnosis. This is among the first studies to evaluate diet in association with ALS function and the first to show that healthy nutrients and antioxidants are associated with better ALS functioning. The findings are published in JAMA Neurology.

Researchers examined the links between nutritional intake and severity of ALS for patients who had ALS symptoms for 18 months or less. The study, which relied on nutrient intake reported using a food questionnaire, followed 302 participants recruited at 16 clinical centers throughout the U.S. The researchers used a validated measure of ALS severity and respiratory function.

The researchers found that “nutrition plays a role both in triggering the disease and why it progresses.” They also found that milk and lunch meats were associated with lower measures of function, or more severe disease. Two different statistical analyses both indicate that diet may help minimize the severity of ALS and point to the role of oxidative stress in ALS severity.
Paper: “Association Between Dietary Intake and Function in Amyotrophic Lateral Sclerosis”
Reprinted from materials provided by: Columbia University

A collaboration of 32 researchers in seven countries has found a genetic mutation they say confers a risk for development of Parkinson’s disease earlier than usual.

The study, published in Brain, is important because the risk comes from a single mutation in the PTEN-induced putative kinase 1 (PINK1) gene. Investigators had believed that this rare form of Parkinson’s developed only when a person inherited mutations in both PINK1 alleles (one from each parent).

PINK1 works with another gene, PARKIN, to ensure that mitochondria in neurons remain healthy. When functioning, proteins from both genes work together to ensure the safe disposal of damaged mitochondria from the cell. Mutations in both PINK1 alleles (or copies) or in both PARKIN alleles mean that the PINK1-PARKIN pathway cannot function, and damaged mitochondria accumulate in a neuron, leading to its death.

This study showed that a specific mutation (p.G411S) in one copy of PINK1 substantially impairs this same pathway by inhibiting the protein produced from other healthy PINK1 allele.

Paper: “Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism”

Reprinted from materials provided by the Mayo Clinic.

A lack of shrinkage in the area of the brain responsible for memory may be a sign that people with thinking and memory problems may go on to develop dementia with Lewy bodies rather than Alzheimer’s disease, according to a new study published in Neurology.

Shrinkage in this hippocampus area of the brain is an early sign of Alzheimer’s disease. Dementia with Lewy bodies is a common form of dementia. Because it has many symptoms in common with Alzheimer’s and Parkinson’s disease, it can be difficult to diagnose. It can include movement problems, sleep disorders and hallucinations.

For the study, 160 people with thinking and memory problems, called mild cognitive impairment, had brain MRI scans at the start of the study to measure the size of the hippocampus. They also had yearly tests for an average of two years. During that time, 61 people, or 38 percent, developed Alzheimer’s disease and 20 people, or 13 percent, progressed to probable dementia with Lewy bodies. It is called probable dementia with Lewy bodies because the disease can be diagnosed definitively only by an autopsy after death. The people who had no shrinkage in the hippocampus were 5.8 times more likely to develop probable dementia with Lewy bodies than those who had hippocampal shrinkage. A total of 17 out of the 20, or 85 percent, of people who developed dementia with Lewy bodies had a normal hippocampus volume; while 37 of the 61, or 61 percent, of people who developed Alzheimer’s disease had shrinkage in the hippocampus.

The relationship was even stronger when researchers looked only at people whose thinking problems did not include memory issues. Dementia with Lewy bodies does not always affect memory; thinking skills that are affected usually include attention, problem solving, and the ability to interpret visual information.

Paper: “Hippocampal volumes predict risk of dementia with Lewy bodies in mild cognitive impairment”
Reprinted from materials provided by AAN.

An international collaboration has shed light on the basal forebrain region, where the degeneration of neural tissue caused by Alzheimer’s disease appears even before cognitive and behavioral symptoms of the disease emerge.

The research, published in Nature Communications, used data obtained from the Alzheimer’s Disease Neuroimaging Initiative database.

The basal forebrain contains very large and densely connected neurons that are particularly vulnerable to the disease. The researchers show that, as Alzheimer’s progresses, degeneration of the basal forebrain predicts subsequent degeneration in temporal lobe areas of the brain involved in memory. This pattern is consistent with other research showing that Alzheimer’s indeed spreads across brain regions over time, but the study challenges a widely held belief that the disease originates in the temporal lobe.

In the two-year study, the researchers were able to determine that individuals with MCI or Alzheimer’s disease showed greater losses in gray matter volume in both the basal forebrain and temporal lobe, compared with cognitively normal controls. Intriguingly, they showed that over the two-year period, degeneration of neural tissue in the basal forebrain predicted subsequent tissue degeneration in the temporal lobe, but not the other way around.

A sampling of spinal fluid from healthy adults can detect an abnormal level of beta amyloid, indicative of Alzheimer’s. Test results showed that temporal lobes looked the same regardless of amyloid level, but the basal forebrain showed notable degeneration among those seemingly healthy adults with abnormal amyloid levels.

Paper: “Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology”
Reprinted from materials provided by Cornell University.

A Japanese research team has found that collapse of the Mitochondria-Associated Membrane (MAM) is a common pathological hallmark to two distinct inherited forms of ALS: SOD1- and SIGMAR1-linked ALS. The research findings were reported in EMBO Molecular Medicine.

Recent studies have revealed that the MAM plays a key role in cellular homeostasis, such as lipid synthesis, protein degradation, and energy metabolism. Intriguingly, a recessive mutation in SIGMAR1 gene, which encodes sigma 1 receptor (Sig1R), a chaperone enriched in the MAM, is causative for a juvenile ALS. In this study, the researchers identified a novel ALS-linked SIGMAR1 mutation, c.283dupC/p.L95fs in a juvenile-onset ALS case. Moreover, ALS-linked Sig1R mutant proteins were unstable and non-functional, indicating a loss-of function mechanism in SIGMAR1-linked ALS.

A loss of Sig1R function induced MAM disruption in neurons. However, it was still unknown whether the MAM alternation was also involved in the other ALS cases. To address this question, the researchers cross-bred SIGMAR1 deficient mice with the other inherited ALS mice which overexpress a mutant form of SOD1 gene. SIGMAR1 deficiency accelerated disease onset of SOD1-ALS mice by more than 20%. In those mice, inositol triphosphate receptor type-3 (IP3R3), a MAM-enriched calcium ion (Ca2+) channel, was disappeared from the MAM. The loss of proper localization of IP3R3 led to Ca2++ dysregulation to exacerbate the neurodegeneration. The researchers also found that IP3R3 was selectively enriched in motor neurons, suggesting that integrity of the MAM is crucial for the selective vulnerability in ALS.

These results provide new perspectives regarding future therapeutics, especially focused on preventing the MAM disruption for ALS patients. Together with the research from other groups, collapse of the MAM is widely observed in the other genetic causes of ALS, and therefore it may be applicable to sporadic ALS patients.

Paper: “Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS”
Reprinted from materials provided by Nagoya University.

Drug researchers have identified several new biological markers to measure the progression of the inherited neurodegenerative disorder Huntington’s disease (HD). Their findings, published in the Journal of Experimental Medicine, could benefit clinical trials that test new treatments for the disease.

One of the earliest events in HD is that mutant huntingtin aggregates disrupt the function of mitochondria, lowering cellular energy levels and causing oxidative damage. The researchers set out to identify markers of HD in non-neural tissues that could be used to track the progression of the disease and its response to P110 or other candidate drugs.

The team found that the levels of mitochondrial DNA, presumably released from dying neurons, were increased in the blood plasma of mice that were starting to develop the symptoms of HD. In contrast, mitochondrial DNA levels decreased at later stages of the disease. P110 treatment corrected plasma mitochondrial DNA back to the levels seen in healthy mice.

The researchers identified several other potential biomarkers that were elevated in HD model mice, including the levels of 8-hydroxy-deoxy-guanosine, a product of oxidative DNA damage, in the urine and the presence of mutant huntingtin aggregates and oxidative damage in muscle and skin cells. The levels of each of these biomarkers were reduced by P110 treatment.

It remains to be seen whether all of these biomarkers are reliable indicators of HD in humans. The team found, however, that mitochondrial DNA levels were significantly elevated in plasma samples from a small number of HD patients.

Paper: “Potential biomarkers to follow the progression and treatment response of Huntington’s disease”
Reprinted from materials provided by Rockefeller University Press.

Researchers have shed new light on the nerve cell processes that lead to Alzheimer’s disease, overturning previously held ideas of how the disease develops and opening the door to new treatment options that could halt or slow its progression.

The study was published in the journal Science.

Studying human brain tissue, the research team identified a protein, kinase p38γ, that is lost as AD progresses. When they reintroduced the protein into the brains of mice, it was shown to have a protective effect against memory deficits associated with the disease.

Two of the hallmarks of Alzheimer’s are the presence of protein plaques (made up of amyloid-beta) and tangles (made up of tau protein) in the brain. The accumulation of these plaques and tangles is associated with cell death, brain atrophy and memory loss.

The research team revealed that a crucial step in the process that leads to tangles has been misunderstood. Previously, scientists believed the plaque-forming protein, amyloid-beta, caused a modification – called phosphorylation – to the tau protein resulting in cell death and, ultimately, Alzheimer’s disease. Increased phosphorylation of tau eventually leads to its accumulation as tangles.

Results from the new study suggest that the phosphorylation of tau initially has a protective effect on neurons, and that amyloid-beta assaults the protective functionality until it is progressively lost. This is the stage at which toxicity levels cause the destruction of neurons and results in the cognitive deficits associated with Alzheimer’s disease.

The study used different mice models and human brain tissue from the Sydney Brain Bank to identify a protein called kinase p38γ, which assisted the protective phosphorylation of tau and interfered with the toxicity created by amyloid-beta.

The next step for the researchers will be to develop their patented discoveries into a novel treatment for humans.

Paper: “Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice”
Reprinted from materials provided by the University of New South Wales.

Synapses, the place where brain cells contact one another, play a pivotal role in the transmission of toxic proteins. This allows neurodegenerative diseases such as Alzheimer’s to spread through the brain, according to new research published in Cell Reports.

During neurodegenerative disease, including Alzheimer’s, toxic proteins are known to spread throughout the brain. As the disease progresses, more and more brain areas are affected.

The researchers now offer proof that synapses are critical to mediate the transmission of toxic protein species and reveal the mechanisms behind this process. They show that the toxic proteins cross from one brain cell to the next by being engulfed by ‘vesicles’, small bubbles in the receiving brain cell. There the vesicles burst and release the toxic proteins.

These findings open new perspectives for the treatment of neurodegenerative diseases. By understanding how toxic proteins are passed on between brain cells, researchers may also be able to identify therapeutic avenues to block this process or to shuttle the toxic proteins to the cellular “waste bins”.

Paper: “Loss of Bin1 Promotes the Propagation of Tau Pathology”
Reprinted from materials provided by VIB-KU Leuven.

Scientists have uncovered new details about how a repeating nucleotide sequence in the gene for a mutant protein may trigger Huntington’s and other neurological diseases.

Researchers used computer models to analyze proteins suspected of misfolding and forming plaques in the brains of patients with neurological diseases. Their simulations confirmed experimental results by other labs that showed the length of repeating polyglutamine sequences contained in proteins is critical to the onset of disease.

The study appears in the Journal of the American Chemical Society.

Glutamine is the amino acid coded for by the genomic trinucleotide CAG. Repeating glutamines, called polyglutamines, are normal in huntingtin proteins, but when the DNA is copied incorrectly, the repeating sequence of glutamines can become too long. The result can be diseases like Huntington’s or spinocerebellar ataxia.

Aggregation in Huntington’s typically begins only when polyglutamine chains reach a critical length of 36 repeats. Studies have demonstrated that longer repeat chains can make the disease more severe and its onset earlier.

The researchers’ simulations showed how sequences with 30 repeats or more are able to fold by themselves without partners into hairpin shapes, which are the building blocks for troublesome aggregates. Thus, for the longer sequences, even a single protein can begin the aggregation process, especially at high concentrations.

The research team also found that at intermediate lengths between 20 and 30 repeats, polyglutamine sequences can choose between straight or hairpin configurations. While longer and shorter sequences form aligned fiber bundles, simulations showed intermediate sequences are more likely to form disordered, branched structures.

The team’s ongoing study is now looking at how the complete huntingtin protein, which contains parts in addition to the polyglutamine repeats, aggregates.

Paper: “The Aggregation Free Energy Landscapes of Polyglutamine Repeats”
Reprinted from materials provided by Rice University.