Tag Archives: science news

Breakthrough in Alzheimer’s Research: What We Thought About Tau Tangles May Be All Wrong

The main hallmark of Alzheimer’s disease is the accumulation of toxic protein species in the brain. These toxic deposits include senile plaques (made of the amyloid-beta protein) and neurofibrillary tangles (made of the tau protein). In general, recent drug development research for Alzheimer’s has focused on targeting amyloid-beta. This is because previous research suggested that amyloid-beta is responsible for initiating a set of chemical reactions that lead to the phosphorylation of tau. This p-tau (phosphorylated tau) is then more prone to sticking to itself and forming tangles. Thus, the thinking was that if we could get rid of amyloid-beta, tau would no longer form tangles, allowing us to eliminate both toxic proteins at once.

normal_vs_alzheimers_brain

Plaques and tangles in a normal and Alzheimer’s disease brain.

However, a study published this week in the journal Science may completely change how we think about amyloid-beta and tau. Researchers from Australia looked at enzymes of the p35 family, which are believed to mediate amyloid-beta’s ability to initiate p-tau formation. They focused on a member of this protein family called p35-delta (p35D), after determining that it was the only p35 protein that localized to synapses (the communication junctions between neurons.)

The exciting part of this study came when the researchers generated Alzheimer’s mice that lacked the gene for p35D. These mice experienced exacerbated symptoms of Alzheimer’s disease, including worsened excitotoxicity, memory loss, and premature death. The researchers determined experimentally that these worsened symptoms were dependent on p35D’s ability to create p-tau. In other words, it seems that the presence of p35D (and in turn, the presence of p-tau) was actually protecting the mice from more severe symptoms of Alzheimer’s disease.

This study is big news in the field of neuroscience because it suggests that the formation of tangles by the p-tau protein may be helpful rather than harmful. Whereas in the past scientists have viewed tangles as a harmful side effect of amyloid-beta plaques, these new results indicate that p-tau may actually be a beneficial reaction to the plaques which keeps their toxicity in check. This is consistent with additional data from the study showing that humans with Alzheimer’s disease have reduced expression of p35D. The authors of the paper suggested that a decline in p35D expression, and in turn a decline in p-tau levels, may be a major contributor to the development of Alzheimer’s disease.

Alzheimer’s researchers around the world are very excited about this paper and the ramifications it could have for future studies. Where previously we had been trying to deplete toxic p-tau, this strategy may actually worsen the disease. Rather, perhaps we should be trying to increase levels of p35D and/or p-tau in early Alzheimer’s patients in order to prevent disease progression. It’s possible that this study may also help explain why approximately 1 in 5 elderly adults contain the signature pathology of Alzheimer’s in their brains and yet do not experience any cognitive deficits. Perhaps these individuals benefit from higher expression of p35D which helps fight of the toxicity of amyloid-beta. Future studies will investigate whether this is indeed the case.

As always, we must interpret these results with caution. Since this study was based in mice, a lot of additional research will be needed to determine whether similar neurochemical pathways occur in humans and, if so, whether these can be utilized to design a preventative treatment for Alzheimer’s. Only time can tell how far-reaching the impacts of this study will be.

 

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A New Possible Mechanism for the Development of Alzheimer’s Disease

Background

Alzheimer’s disease is characterized by the buildup of toxic protein species in the brain. One of these proteins is tau. Tau normally is involved with stabilizing the cytoskeleton that gives neurons their structure. However, in people with Alzheimer’s disease, certain enzymes attach too many phosphate groups to tau. Molecules of this hyperphosphorylated tau can stick to each other to form tangles of fibers that accumulate inside of neurons.

It was originally assumed that these tau tangles contributed to neuronal death in Alzheimer’s disease. However, it has since been discovered that less than 17% of neurons in an Alzheimer’s brain contain tangles, even in the most advanced disease stages. Additionally, it was recently shown that the tangles are not associated with memory deficits or neuronal death in a mouse model. This has led some researchers to speculate that the soluble form of tau, which does not accumulate into tangles, might actually be the toxic species.

New Results

In a study published last week in Nature Medicine, researchers uncovered a possible mechanism for the toxicity of soluble tau. At the time, they were studying mice with a mutation that causes them to express high levels of tau. The researchers noticed that a particular fragment of tau called ∆tau314 (named so because it had been cleaved after the 314th amino acid) was more abundant in the mice that had greater memory impairment. They then looked at human brain tissue from 85 elderly subjects and found that tau fragments similar to ∆tau314 were present at significantly higher levels in cognitively impaired subjects compared to non-impaired controls. They demonstrated experimentally that this fragment was soluble and did not form the large tau tangles.

Subsequent experiments determined that an enzyme called caspase-2 was capable of cutting the ∆tau314 fragment from full-length tau. When they reduced the levels of caspase-2 in the brains of their Alzheimer’s mice, the levels of ∆tau314 decreased and the mice showed complete reversal of cognitive impairment.

The researchers were also able to determine the mechanism by which ∆tau314 leads to cognitive impairment. Previous studies had shown that in Alzheimer’s disease, tau improperly localizes to dendritic spines, the part of the neuron where it receives communicative inputs from other neurons. These communication sites can malfunction when too much tau is present. The researchers created mice expressing a form of tau that was resistant to cleavage at the 314th amino acid. They found that this form of tau did not localize to dendritic spines. Additionally, the mice did not experience any cognitive impairment or neurodegeneration, despite expressing high levels of this modified tau.

The main conclusion of this study was that in order for tau to induce the pathology of Alzheimer’s disease, it must first be cut at the 314th amino acid by caspase-2. This is an intriguing result, as it suggests that caspase-2 might be a useful therapeutic target for future drug research. In theory, if we can prevent caspase-2 from cutting tau, this could in turn prevent tau from causing malfunctions in dendritic spines. In addition, this study provides further support for the hypothesis that soluble tau, rather than insoluble tau tangles, is the more harmful species in Alzheimer’s disease.

An important caveat of this study is that it was performed almost exclusively on mice. These mice are only a simulation of human Alzheimer’s disease, and thus the same mechanisms may not translate to humans. Though significantly higher levels of ∆tau314 were found in cognitively impaired human brains, further research is needed to determine whether blocking caspase-2 cleavage of tau offers the same benefits in humans as it does in mice.

Additionally, the mice in question only simulated the tau pathology of Alzheimer’s. Tau is only one aspect of human Alzheimer’s disease. Other relevant pathologies include beta-amyloid plaques, neuropil threads, and neuroinflammation. Thus, it seems unlikely that eliminating the toxicity of tau could entirely reverse the disease in humans. A more likely scenario is that a caspase-2 drug therapy might be combined with other drugs that target the other pathological agents.

Despite these caveats, this paper represents an exciting development in Alzheimer’s disease research. Only time can tell whether it will translate to human drug candidates down the road.

 

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Immune System Protein Reverses Alzheimer’s Disease in Mice

Background

The immune system is closely involved with the pathology of Alzheimer’s disease. In healthy brains, immune cells called microglia work to destroy or clear away harmful substances in the brain. However, the gradual accumulation of a toxic protein called amyloid-beta can disrupt microglial function, causing them to release potentially-harmful inflammatory molecules. The inflammatory pathways activated by microglial signaling contribute to the development and progression of Alzheimer’s disease. A 2012 study showed that inhibiting some of these pathways can combat Alzheimer’s in animal models.

A protein called interleukin-33 (IL-33) is an important mediator of inflammation and is involved with multiple infections and autoimmune diseases. Genetic studies have demonstrated that people with certain variants in the IL-33 gene have an increased risk of Alzheimer’s. Additionally, the brains of people with Alzheimer’s have decreased levels of IL-33 gene expression compared to healthy brains. This has led some to speculate that lower levels of IL-33 may promote the buildup of amyloid-beta that occurs in Alzheimer’s disease.

New Study

Research published recently in the journal PNAS attempted to address whether IL-33 could be a therapeutic target for Alzheimer’s. The researchers used mice that were genetically designed to simulate Alzheimer’s pathology and injected them with the IL-33 protein. After two days of injections, the mice showed significantly improved long-term potentiation, the process strengthening connections between neurons that is critical for learning and memory. After seven days, the mice also had an improved response to fear conditioning, a test of contextual memory retrieval. Additionally, the mice had approximately 20% lower levels of amyloid-beta plaques in their brains. The researchers demonstrated that this reduction was due to the activation of alternate inflammatory pathways, which enhanced the ability of microglia to destroy the plaques.

Additional research is needed to determine the mechanism by which IL-33 improves Alzheimer’s symptoms in these mice. It is also unclear whether these results will generalize to humans, as the mouse models are more similar to human early-onset Alzheimer’s disease and bear significant differences from the more common late-onset form. However, the research presents an intriguing new approach to combatting Alzheimer’s by enhancing the brain’s own immune system.

 

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How to Be a Smart Consumer of Science News

You can hardly turn on the news or look at Facebook’s “trending” list without hearing about the latest results of some scientific study. However, the science news that is reported to the general public is often misleading. Reporters are known for twisting around a study’s results in order to make a catchier headline. If you’ve seen John Oliver’s discussion of this topic on “Last Week Tonight” (click here to watch it, it’s very interesting), you know what a serious problem this can be. Inaccurate or misconstrued scientific results have led to people believing that vaccines cause autism or that global climate change is not caused by human activity. In this article, I will provide you with five questions you should always ask when evaluating the validity of a science news claim. Keeping these questions in mind will help make sure you can tell science from pseudoscience.

Question #1: What news source am I viewing or reading?

As we all know, some news sources are more accurate and unbiased than others. Even seemingly-reputable sources like Scientific American have been guilty of representing the results of scientific studies out of context. Whenever possible, try to find a link to the original science paper, which is often provided in online news articles. This will allow you to view the results in a format that’s less likely to be biased. Pay attention to the journal in which the paper was published. Publications in larger journals like Science, Nature, Neuroscience, or PLoS1 are more likely to be both valid and important than those published in smaller, more specialized journals.

Question #2: How statistically significant were the results?

Statistical significance is the probability that the results of the study arose by random chance, rather than as the result of the experimental conditions. Each study will have a particular threshold that the ratios must be beneath for the results to be declared statistically significant. A common threshold is 0.05, meaning that there is a 5% chance of the results being due to random chance. This may seem small, but it means that there’s a 1 in 20 chance of the results being invalid. For results that are more likely to be valid, look for studies that have a lower significance threshold, such as 0.01 or 0.001.

Question #3: What model organisms were studied?

Clinical trials and other experiments conducted directly on humans are the most likely to have results that generalize to other humans. However, these often require years of supporting data to be authorized, so the majority of neuroscience and biology studies are conducted on animals designed to act as “models” for humans. Common animal models include bacteria, yeast, frogs, fruit flies, zebrafish, mice, and rats. Mice are the most common model for Alzheimer’s disease, though lately their accuracy in representing the disease symptoms has been brought into question. Whenever experiments are conducted on animals, be sure to take their results with a grain of salt.

Question #4: What were the sample size and timeframe?

Sample size is the number of humans or animals observed during the study. For noninvasive research such as online surveys, sample sizes are often hundreds or thousands of people. In contrast, studies that require surgery might have a sample size of only a few dozen. The smaller the sample size, the less likely that the results of the study will generalize to a larger population. On a similar note, you should also pay attention to the timescale of the study. Particularly for age-related diseases like Alzheimer’s, human studies conducted for only a few weeks or months may not be as informative as those conducted for many years.

Question #5: Does the study provide correlational or causational evidence?

This is probably the most important question of all, and it’s also the one that is most often ignored by popular reporting of science news. Correlational evidence (sometimes called epidemiological evidence) is based on observation, while causational evidence is based on random experimental assignment. Let me explain this distinction through an example. A famous 2002 study observed that people who consumed higher levels of caffeine were less likely to be diagnosed with Alzheimer’s disease. This is correlational because it shows that caffeine is correlated with a reduced Alzheimer’s risk, but cannot prove that it necessarily causes a reduced risk. It’s possible that people who consume more caffeine might also be more likely to exercise, have an active social life, or be more educated. In this case, one of these other factors (which are called confounding variables) might be the cause of the reduced risk, rather than the caffeine itself. In contrast, a causational study on this subject was conducted in 2006. The researchers fed lab mice different levels of caffeine and found that those with higher caffeine intake had reduced levels of amyloid plaques in their brains. In this case, the caffeine is more likely to be the cause of this result because all other variables were carefully controlled and the mice were assigned their caffeine intake randomly. An easy way to remember this difference is that correlation typically comes from studies where the subjects have free choice, whereas causation can only be established when the subjects are randomly assigned a condition by the experimenter.

 

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