Systemic falsification found in article on Alzheimer’s disease mechanism – News Home


A decades-long scientific hoax has been exposed – a neuroscientist has systematically fabricated data about the role of beta-amyloid in the development of Alzheimer’s disease. Two separate image analyses simultaneously revealed that the author simply “smeared” the beta-amyloid strips he needed on the protein electrophoresis results. Perhaps this will force us to reconsider the leading theory of the origin of the disease.

lumps and balls

“I got lost in my own yard. I didn’t know where I was going, I forgot how to get home. <...> So far I have managed to get back. <...> It’s not ignorance that scares me, it’s the question of when I get to that line, beyond which I’ll never be able to come back.</...></...> A character in the docu-series “Alzheimer’s Project: A Documentary of Lost Memories” describes his symptoms this way (Alzheimer’s Project)。 Alzheimer’s disease It is the most common cause of dementia in the her fate Take up From 60% to 80% of Alzheimer’s cases, according to US statistics, more than 10% of people over the age of 65 suffer from the disease.

The above quote is a good description of how terrifying Alzheimer’s disease can be – its steady progression inevitably leads to a complete loss of consciousness, personality, ability to communicate and serve oneself. If he did not die of other causes during this period, he died. This clinical presentation resembles another group of diseases — Prion disease, develops due to incorrect folding of proteins in the neurons of the brain. The only difference is that Alzheimer’s disease progresses much more slowly and is unlikely to be infected.

Similarity is not accidental.It has long been known that Alzheimer’s disease is also associated with the wrong structure of proteins, especially proteins applicationon neuronal membranes. This protein has many functions – for example, it is involved in synapse formation and preventing infection. It is cleaved by α-, β- and γ-secretase to form peptides of different lengths depending on the cleavage point. Some of these peptides were able to stick together to form dense clumps (it would be more correct to call them plaques) that, when stained with histological dyes, resembled starch granules (Figure 1).Therefore, the substance of these plaques is called amyloid (From the Greek word ἄμυλον – starch).

Amyloid deposits in the intercellular spaces outside neurons. When too much of this protein “junk” accumulates, nerve cells begin to die.

Since there are many amyloids (they can be formed not only from APP, but not only in the brain), the amyloid formed from APP is called beta-amyloid, or Abeta. In fact, the name of the APP protein itself stands for Amyloid-beta precursor protein, the precursor protein for beta-amyloid.

The role of this protein in disease development has been most studied – firstly, beta-amyloid (as previously described) is clearly visible under the microscope during pathological dissection. Second, all early-onset familial Alzheimer’s disease are caused by mutations in the APP gene or its metabolic genes (encoding presenilin 1 and presenilin 2 proteins).

But the fatal chain of events in the brain doesn’t end with beta-amyloid (Figure 2). Inside the neuron, another protein begins to’s about tau proteinusually stable microtubules. They are like rails, passing through the neuron’s long process (axon), various substances are transported along the axon. In Alzheimer’s disease, tau proteins begin to tangle into globules, and the brain functions like a railway, with construction debris every kilometer.The process also involves neurotransmitters Glutamate – It releases and overactivates its receptors uncontrollably, leading to cell death.

米。 2.阿尔茨海默病是基于大脑蛋白质结构的破坏

The most plausible view to date is that β-amyloid is the root of all diseases, and it is the accumulation of β-amyloid plaques outside neurons that triggers the cascade of pathological changes inside neurons, including tau protein entanglement. Glutamate tangles and leaks… This theory is called Amyloid Cascade Theory.

Still, scientists sometimes have questions, especially related to the discovery of unexpected pathogenesis-related links and factors that haven’t been incorporated into the amyloid cascade theory, like an extra piece in the puzzle.For example, certain alleles of a gene apolipoprotein E Increased risk of Alzheimer’s disease.Surprisingly, the main function of this protein is to be involved in transport cholesterol. So it turns out that cholesterol is also somehow “involved” in the development of Alzheimer’s disease. But how remains unclear. Overall, one wonders whether beta-amyloid accumulation is a major link in disease pathogenesis, or whether it is triggered by some other mechanism, such as a violation of cholesterol metabolism or even infection and inflammation!

The question of the pathogenesis of this disease is important because without understanding it in detail, we are effectively deprived of the opportunity to develop at least some effective treatments. Currently, drugs that affect the action of neurotransmitters (eg, rivastigmine and memantine) are used to treat it. They can slightly slow the deterioration of memory and thinking, but do not stop neurons from dying, so they lose their potency over time. Scientists haven’t given up trying to create a drug that targets the mechanism by which Alzheimer’s disease develops — and essentially “targets” the protein beta-amyloid precisely.

copy and paste

In 2006, the young neuroscientist Sylvain Lesne (Sylvain Lane) published in journals with co-authors nature article Specific beta-amyloid assembly in the brain impairs memorythat time seem Revolutionary science. Even so, at the tissue level, Alzheimer’s disease is still associated with the accumulation of amyloid plaques, but the exact role of beta-amyloid is not fully understood.

Lesne and colleagues claim to have discovered a 56-kDa β-amyloid oligomer, which they referred to as Aβ*56 for short. The first paper hypothesized that introducing this amyloid into experimental rodents helped them develop the changes characteristic of Alzheimer’s disease in humans. Well, like prions! In subsequent articles, the topic of Aβ*56 has developed, but one message has remained the same: these 56-kilodalton oligomers are the source of all molecular problems that occur in the neurons of the diseased.

In Lesne’s work, the primary method for detecting protein aggregates of a given molecular weight is Western blotting.Western blot) — protein electrophoresis with antibody detection. Briefly, proteins of different molecular weights are “accelerated” in an electric field, forming bands in polyacrylamide gels. Of course, every article contains images of such electropherograms. Lesne’s article was cited thousands of times, and no one suspected something was wrong until everything was stumbled upon.

The story of the revelations began with the fact that a lawyer needed the help of experts in the delicate case of a pharmaceutical company that launched the drug simufilam. The attorney’s client, a neuroscientist, sought to question the drug’s findings, saying they were falsified. The lawyer is Matthew Shrag (Matthew Schrager) – a neuroscientist and psychiatrist at Vanderbilt University – and brought him in as an expert. Shreg managed to determine that there was indeed a forgery. But along the way, he discovered another interesting thing.

For the exam, he visited the post-publication review service PubPeer, where scientists can comment on colleagues’ work. He was looking for articles on Alzheimer’s disease that critically reviewed them. But it wasn’t just the article about simufilam that caught his attention. Lesne’s work also turned out to be “popular”—colleagues raised many questions about the reliability of his published Western blot images. Shreg became interested and decided to analyze the images in detail to identify signs of “painting”.

He conducted a computer analysis of Lesne’s archive of publications over the years, combining parts of the images with each other. As a result, the neuroscientist article found many precisely matched bands in different places, which cannot be explained by coincidence. The fact is that during western blotting, protein bands form “blots” with jagged edges, the shape of which is largely random. An exact match can only indicate one thing – that Sylvain Lesnay “painted” some stripes using the copy-paste method on the computer. The “painting” was precisely located within the area the researchers assigned to Aβ*56. on the diagram. Figure 3 clearly illustrates the technique used by Shreg to detect duplicated fragments in the image.

米。 三、如何判断电泳图上的数据是抄袭造假

Who to trust now?

Shreg described the findings as post in the latest issue of the magazine science And for a while it became one of the major news in the scientific world. Before publishing the results of this survey, science Two more image analysis experts were brought in, who re-examined Lesne’s electropherograms and generally confirmed Schrag’s arguments. There’s really been a massive fraud over the years.

This is an unprecedented analytical effort to detect fraud in scientific research and was published in science. Andrei Zajakin – Russian physicist and member of the Dissernet community, which works to identify scientific falsification in Russia, – Comment This is true: “Shreg’s work is jaw-dropping – you could call it “One Man’s Dissernet,” with hundreds of slips of paper passing through his hands”。

After Shrag’s investigation, other embarrassing details about amyloid Aβ*56 began to emerge. It turned out that no one could pick it out at all! But only one group of researchers has published such negative results (GM Shankar et al., 2008. Amyloid beta-protein dimers isolated directly from Alzheimer’s disease brains impair synaptic plasticity and memory). Simply because negative results are posted much less frequently than positive results. At the time of publication, no one noticed that Aβ*56 was not found for some reason.

So what now – the amyloid cascade hypothesis proven wrong? At present, it is too early to draw such a conclusion. The concept of beta-amyloid as the most important trigger for Alzheimer’s disease is not only “held” by Lesnay and his mythical Aβ*56 work: there is so much evidence to support beta-amyloid as the culprit, from Genetics to Microscopy. We now only know that Aβ*56 was specifically invented and mapped, but the possible role of other forms of β-amyloid has likewise been abolished. Even other oligomers may play imaginary characters that Lesne attributes to him.Schreger himself He says“The broader history of amyloid oligomers may survive this question, but the origin of this condition should be considered.”

What happened does raise a more important question: how much can we trust science, and how will science protect itself from such stories in the future?Careful review of an article’s images and data before publication can prevent this manipulation, but it is unclear whether editors of scientific journals will be able to develop some kind of universal standard and follow it (although call for this It doesn’t sound like the first time).

The moral of the whole story can be taken as a quote from Matthew Shrag, from interview in the magazine science:“You can cheat to publish an article. You can get a degree by cheating. You can trick yourself into winning funding. But you can’t cure disease by cheating. Biology doesn’t care.»

resource: C. Peeler. Stain on the field? // science. 2022. DOI:10.1126/science.add9993。

George Kuragin

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