amyloid plaque

OB Science Time: The Castor Disease

Episode 3x03 had a lot of science in it, so it’s time for a second edition of OB Science Time to discuss the science behind the Castor Disease, or “glitching”.

Scott says, upon examining Seth’s brain that “it looks like Swiss cheese” and he mentions encephalopathy as well as Creutzfeldt-Jakob disease. Encephalopathy is an umbrella of diseases categorized by an altered mental state, including symptoms such as loss of cognitive function, subtle personality changes, and inability to concentrate. We certainly saw these symptoms in Seth, with his inability to perform well on Paul’s syllogism test, as well as his violent outburts and his mutterings in the stairwell before his final episode.

Creutzfeldt-Jakob disease is caused by prions, which are misfolded proteins that then act as an agent to convert their properly folded counterparts into more prions. The classic result of these prions is a change in the gray matter of the brain, causing large vacuoles to form, giving the appearance of Swiss Cheese. Symptoms of this disease include memory loss, personality change, and hallucinations, as well as jerky movements and seizures.

My guess is that the Castor disease functions in a similar manner as these diseases. Scott also mentioned the presence of amyloid plaques in Seth’s brain, which are protein aggregates. These aggregates, which could be made up of prions, could be causing neurodegeneration, leading to the Castor glitches and altered mental states.

It will be interesting to see what Cosima and Scott do with this knowledge, and more importantly, how the Castor clones will go about finding a cure for their malfunction.

My ask is always open for any questions or comments, and you can find more OB Science Time here!! :D

Discovery of Neurotransmission Gene May Pave Way for Early Detection of Alzheimer's Disease

A new Tel Aviv University study identified a gene coding for a protein that turns off neurotransmission signaling, which contributes to Alzheimer’s disease (AD).

The gene, called RGS2 (Regulator of Protein Signaling 2), has never before been implicated in AD. The researchers report that lower RGS2 expression in AD patient cells increases their sensitivity to toxic effects of amyloid-β. The study, published in Translational Psychiatry, may lead to new avenues for diagnosing Alzheimer’s disease — possibly a blood test — and new therapies to halt the progression of the disease.

The research was led by Dr. David Gurwitz of the Department of Human Molecular Genetics and Biochemistry at TAU’s Sackler School of Medicine and Prof. Illana Gozes, the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Head of the Elton Laboratory for Molecular Neuroendocrinology at TAU’s Sackler School of Medicine; and a member of TAU’s Adams Super Center for Brain Studies and TAU’s Sagol School of Neuroscience. Also participating in the research were their PhD student Adva Hadar and postgraduate student Dr. Elena Milanesi, in collaboration with Dr. Noam Shomron of the Department of Cell and Developmental Biology at TAU’s Sackler Faculty of Medicine and his postgraduate student Dr. Daphna Weissglas; and research teams from Italy and the Czech Republic.

Identifying the suspect

“Alzheimer’s researchers have until now zeroed in on two specific pathological hallmarks of the chronic neurodegenerative disease: deposits of misfolded amyloid-β (Aβ) peptide plaques, and phosphorylated tau protein neurofibrillary tangles found in diseased brains,” Dr. Gurwitz said. “But recent studies suggest amyloid-β plaques are also a common feature of healthy older brains. This raises questions about the central role of Aβ peptides in Alzheimer’s disease pathology.”

The researchers pinpointed a common suspect — the RGS2 gene — by combining genome-wide gene expression profiling of Alzheimer’s disease blood-derived cell lines with data-mining of previously published gene expression datasets. They found a reduced expression of RGS2 in Alzheimer’s disease blood-derived cell lines, then validated the observation by examining datasets derived from blood samples and post-mortem brain tissue samples from Alzheimer’s patients.

“Several genes and their protein products are already known to be implicated in Alzheimer’s disease pathology, but RGS2 has never been studied in this context,” Dr. Gurwitz said. “We now propose that whether or not Aβ is a primary culprit in Alzheimer’s disease, neuroprotective mechanisms activated during early disease phases lead to reduced RGS2 expression.”

Sensitizing brain neurons to potential damage

The new TAU study furthermore proposes that reduced RGS2 expression increases the susceptibility of brain neurons to the potentially damaging effects of Aβ.

“We found that reduced expression of RGS2 is already noticeable in blood cells during mild cognitive impairment, the earliest phase of Alzheimer’s,” Dr. Gurwitz observed. “This supported our theory that the reduced RGS2 expression represents a ‘protective mechanism’ triggered by ongoing brain neurodegeneration.”

The team further found that the reduced expression of RGS2 was correlated with increased Aβ neurotoxicity. It acted like a double-edged sword, allowing the diseased brain to function with fewer neurons, while increasing damage to it by accumulating misfolded Aβ.

“Our new observations must now be corroborated by other research groups,” Dr. Gurwitz concluded. “The next step will be to design early blood diagnostics and novel therapeutics to offset the negative effects of reduced expression of the RGS2 protein in the brain.”

Engineered protein prevents dementia in mice carrying Alzheimer's genes

A newly-developed protein has successfully prevented dementia from occurring in lab mice carrying human Alzheimer’s genes, raising the possibility for development of new treatments for the disease. 

Hanna Lindberg, a researcher at KTH Royal Institute of Technology, worked with colleagues in Sweden and New York to develop a so-called binding protein that could target amyloid beta peptides, which are associated with Alzheimer’s disease.

When equipped with the binding protein, the researchers found that laboratory mice carrying the genes for human Alzheimer’s did not develop disease-related memory impairment or impaired cognitive ability, Lindberg says.

The proteins also prevented the occurrence of amyloid plaques on the brains of lab mice. These plaques result from the large-scale production of amyloid beta peptides in the brains of Alzheimer’s patients.

“We greatly reduced the amounts of amyloid beta peptides in the brains of these mice,” Lindberg says. 

(Image caption: Interaction between affibody-molecules (purple) and amyloid beta (orange). PDB.org: 2OTK)

Binding proteins get their name from their ability to act as an agent in binding molecules together. These proteins mimic the function of antibodies but are much smaller. The proteins used by Lindberg and her team are based on affibodies — an engineered class of proteins that can be designed to bind tightly and specifically against various diseases’ proteins.

“In our case, we have created lots of variations of the same binding protein to find the optimal version for the target peptides which are associated with Alzheimer’s,” Lindberg says.

So far, she says, the results are promising. “The mice that received the treatment with affibody molecules behave just like healthy animals when it comes to memory and cognitive ability,” she says.

The test results could provide the basis for work on new treatments for Alzheimer’s, Lindberg says, adding that a drug could be available within a decade if all the conditions are favorable.

“Alzheimer’s is the most common dementia disease today,” she says. “There are medicines for the symptoms, but no effective treatment method. The medications do not attack the fundamental disease mechanisms, and they tend to become inactive after a while.”

According to the Alzheimer’s Association, 35 million people suffer from Alzheimer’s disease today, and this figure will triple by the year 2050. It usually develops slowly and gradually gets worse as brain function declines and brain cells eventually wither and die. Ultimately, Alzheimer’s is fatal, and currently, there is no cure.

Stefan Ståhl, dean of the School of Biotechnology at KTH and a professor of molecular biotechnology, has been the main supervisor of Hanna Lindberg.

“I recently came home from a project meeting at New York University,” Ståhl says. “It was clear to me that the results achieved by Hanna protein were so good that they are on par with other protein-based preventive medicines that have been used in clinical trials for Alzheimer’s disease. In most cases, these are monoclonal antibodies. No such drugs are on the market today.”

Genetically Engineered Mice Suggest New Model for How Alzheimer’s Disease Causes Dementia

Using a novel, newly developed mouse model that mimics the development of Alzheimer’s disease in humans, Johns Hopkins researchers say they have been able to determine that a one-two punch of major biological “insults” must occur in the brain to cause the dementia that is the hallmark of the disease. A description of their experiments is published online in the journal Nature Communications.

For decades, Alzheimer’s disease, the most common cause of dementia, has been known to be associated with the accumulation of so-called neurofibrillary tangles, consisting of abnormal clumps of a protein called tau inside brain nerve cells, and by neuritic plaques, or deposits of a protein called beta-amyloid outside these cells along with dying nerve cells, in brain tissue.

In Alzheimer’s disease, tau bunches up inside the nerve cells and beta-amyloid clumps up outside these cells, mucking up the nerve cells controlling memory, notes Philip C. Wong, Ph.D., professor of pathology at the Johns Hopkins University School of Medicine.

What hasn’t been clear is the relationship and timing between those two clumping processes, since one is inside cells and one is outside cells, says lead and corresponding study author Tong Li, Ph.D., an assistant professor of pathology at Johns Hopkins. Prior studies of early-onset Alzheimer’s disease have suggested that the abnormal accumulation of beta-amyloid in the brain somehow triggers the aggregation of tau leading directly to dementia and brain cell degeneration. But the new research from Li, Wong and colleagues suggests that the accumulation of beta-amyloid in and of itself is insufficient to trigger the conversion of tau from a normal to abnormal state. Instead, their studies show, it may set off a chain of chemical signaling events that lead to the “conversion” of tau to a clumping state and subsequent development of symptoms.

“For the first time, we think we understand that the accumulation of amyloid plaque alone can damage the brain, but that’s actually not sufficient to drive the loss of nerve cells or behavioral and cognitive changes,” Wong says. “What appears to be needed is a second insult — the conversion of tau — as well.”

In humans, the lag between development of the beta-amyloid plaques and the tau tangles inside brain nerve cells can be 10 to 15 years or more, Li says, but because the lifetime of a mouse is only two to three years, current animal models that successfully mimic the appearance of beta-amyloid plaques did not offer enough time to observe the changes in tau.

To address that problem, the Johns Hopkins researchers genetically engineered a mouse model that used a tau fragment to promote the clumping of normal tau protein. They then cross-bred these mice with mice engineered to accumulate beta-amyloid. The result was a mouse model that developed dementia in a manner more similar to what happens in humans, Li says.

The researchers found during brain dissections of the animals that the presence of beta-amyloid plaque alone was not sufficient to cause the biochemical conversion of tau, the repeat domain of tau — the part of tau protein that is responsible for the conversion of normal tau to an abnormal state — alone was insufficient for the conversion of tau, beta-amyloid plaques must be present in the brain for the conversion of tau and the tau fragments could “seed” the plaque-dependent pathological conversion of tau.

One implication of the new research, Wong says, is to possibly explain why some drugs designed to attack the disease after the conversion of tau haven’t worked. “The timing may be off,” he says. “If you were to intervene in the time period before the conversion of tau, you might have a good chance of ameliorating the deficits, brain cell loss and ensuing consequence of the disease.”

The work also suggests that combination therapy designed to prevent both the beta-amyloid plaque formation as well as pathological conversion of tau may provide optimal benefit for Alzheimer’s disease, the researchers say. Their mouse model could be used to test new therapies.

An estimated 5.4 million Americans are living with Alzheimer’s disease, according to 2016 statistics from the Alzheimer’s Association. There is no cure, but there are some medications that may help stabilize cognition for a limited time or help with related depression, anxiety or hallucinations.

November 3, 1906: Alois Alzheimer presents a novel kind of early-onset dementia

110 years ago, on November 3, 1906, German psychiatrist Alois Alzheimer reports for the first time before a congress in Tübingen about a novel kind of early-onset dementia accompanied with massive loss of cerebral matter, deposition of amyloid plaques and occureence of neurofibrillar tangles in the cortex.

In 1901, Alzheimer was introduced to a 51 year-old patient of the Frankfurt mental asylum called Auguste Deter.

She had been taken there by her husband after she had shown disastrous changes in her personality and had become unable to lead the household over the course of only one year. Alzheimer recorded the first interrogation with Auguste Deter as followed:

Alzheimer: „What is your name?“
Deter: „Auguste.“
Alzheimer: „Family name?“
Deter: „Auguste.“
Alzheimer: „What’s the name of your husband?“
Deter (hesitant): „I believe… Auguste.“
Alzheimer „Your husband?“
Deter: „Oh, I see.“
Alzheimer: „How old are you?“
Deter: „51.“
Alzheimer: „Where do you live?“
Deter: „Oh, you have been visiting us before.“
Alzheimer „Are you married?“
Deter: „Oh, I am so confused.“
Alzheimer: „Where are you here?“
Deter: „Here and everywhere, here and now, you must not take offense.“
Alzheimer: „Where are you here?“
Deter: „We will be going to live here.“
Alzheimer: „Where is your bed?“
Deter: „Where might it be?“
Alzheimer: „Write down number five.”
Deter: *writes down ‘a woman’*
Alzheimer: „Write down number eight.”
Deter (while writing down ‘Auguste’): „I have lost myself, so to speak.”

It was obvious that Auguste Deter was very well aware of her helplessness and very distressed about it, with her mood rapidly changing between anxiety, weepiness, mistrust and denial. Alzheimer became highly interested in this case as she was only 51 years old, much younger than most patients with dementia. He refused to give her away to another asylum, even after he had moved from Frankfurt to Munich, and even though she became aggressive against the other resident patients. In his notes, Alzheimer called her condition the “disease of forgetting”.

On April 9, 1906, Alzheimer was informed that Auguste Deter had died from a sepsis, untreatable in the days before antibiotics. In the final stages of her disease, she was unable to walk and bound to bed, where she developed decubitus, which became infected. Alzheimer had her brain sent to Munich and investigated it microscopically with the help of two Italian physicians, using state-of-the-art staining techniques. These investigations were the foundation of the characterization of Auguste Deter’s condition as a newly discovered disease. His initial talk in Tübingen, however, left the audience unimpressed, and he was sent away without further discussion, questions or comments. Two papers describing the condition and the associated pathological histology were published soon, and in 1910, Alzheimer’s boss, Emil Kraepelin referred to the syndrome as “Alzheimer’s disease” in a book chapter, a name that remained.

Alzheimer died in 1915 from complications of what probably was a streptococcus infection in 1912, causing heart, kidney, and rheumatic conditions. Due to his short life, he was never able to discuss his findings with a broad scientific community.

In the early 1990s, medical researchers began doubting whether Alzheimer’s observations matched with today’s diagnosis of Alzheimer’s disease. Through lucky circumstances, Alzheimer’s notes and his original microscopic slides were found in 1997 in an extremely well-preserved state, so that all doubts could be removed.