amyloid plaques

Call it Mighty Mouse: Breakthrough leaps Alzheimer's research hurdle

Study reveals crucial mechanisms contributing to the disease

July 31, 2019

Science Daily/University of California - Irvine

University of California, Irvine researchers have made it possible to learn how key human brain cells respond to Alzheimer's, vaulting a major obstacle in the quest to understand and one day vanquish it. By developing a way for human brain immune cells known as microglia to grow and function in mice, scientists now have an unprecedented view of crucial mechanisms contributing to the disease.

 

The team, led by Mathew Blurton-Jones, associate professor of neurobiology & behavior, said the breakthrough also holds promise for investigating many other neurological conditions such as Parkinson's, traumatic brain injury, and stroke. The details of their study have just been published in the journal Neuron.

 

The scientists dedicated four years to devising the new rodent model, which is considered "chimeric." The word, stemming from the mythical Greek monster Chimera that was part goat, lion and serpent, describes an organism containing at least two different sets of DNA.

 

To create the specialized mouse, the team generated induced pluripotent stem cells, or iPSCs, using cells donated by adult patients. Once created, iPSCs can be turned into any other type of cell. In this case, the researchers coaxed the iPSCs into becoming young microglia and implanted them into genetically-modified mice. Examining the rodents several months later, the scientists found about 80-percent of the microglia in their brains was human, opening the door for an array of new research.

 

"Microglia are now seen as having a crucial role in the development and progression of Alzheimer's," said Blurton-Jones. "The functions of our cells are influenced by which genes are turned on or off. Recent research has identified over 40 different genes with links to Alzheimer's and the majority of these are switched on in microglia. However, so far we've only been able to study human microglia at the end stage of Alzheimer's in post-mortem tissues or in petri dishes."

 

In verifying the chimeric model's effectiveness for these investigations, the team checked how its human microglia reacted to amyloid plaques, protein fragments in the brain that accumulate in people with Alzheimer's. They indeed imitated the expected response by migrating toward the amyloid plaques and surrounding them.

 

"The human microglia also showed significant genetic differences from the rodent version in their response to the plaques, demonstrating how important it is to study the human form of these cells," Blurton-Jones said.

 

"This specialized mouse will allow researchers to better mimic the human condition during different phases of Alzheimer's while performing properly-controlled experiments," said Jonathan Hasselmann, one of the two neurobiology & behavior graduate students involved in the study. Understanding the stages of the disease, which according to the Alzheimer's Association can last from two to 20 years, has been among the challenges facing researchers.

 

Neurobiology & behavior graduate student and study co-author Morgan Coburn said: "In addition to yielding vital information about Alzheimer's, this new chimeric rodent model can show us the role of these important immune cells in brain development and a wide range of neurological disorders."

https://www.sciencedaily.com/releases/2019/07/190731125448.htm

A comprehensive map of how Alzheimer's affects the brain

Analysis of genes altered by the disease could provide targets for new treatments

May 1, 2019

Science Daily/Massachusetts Institute of Technology

MIT researchers have performed the first comprehensive analysis of the genes that are expressed in individual brain cells of patients with Alzheimer's disease. The results allowed the team to identify distinctive cellular pathways that are affected in neurons and other types of brain cells.

 

This analysis could offer many potential new drug targets for Alzheimer's, which afflicts more than 5 million people in the United States.

 

"This study provides, in my view, the very first map for going after all of the molecular processes that are altered in Alzheimer's disease in every single cell type that we can now reliably characterize," says Manolis Kellis, a professor of computer science and a member of MIT's Computer Science and Artificial Intelligence Laboratory and of the Broad Institute of MIT and Harvard. "It opens up a completely new era for understanding Alzheimer's."

 

The study revealed that a process called axon myelination is significantly disrupted in patients with Alzheimer's. The researchers also found that the brain cells of men and women vary significantly in how their genes respond to the disease.

 

Kellis and Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory, are the senior authors of the study, which appears in the May 1 online edition of Nature. MIT postdocs Hansruedi Mathys and Jose Davila-Velderrain are the lead authors of the paper.

 

Single-cell analysis

The researchers analyzed postmortem brain samples from 24 people who exhibited high levels of Alzheimer's disease pathology and 24 people of similar age who did not have these signs of disease. All of the subjects were part of the Religious Orders Study, a longitudinal study of aging and Alzheimer's disease. The researchers also had data on the subjects' performance on cognitive tests.

 

The MIT team performed single-cell RNA sequencing on about 80,000 cells from these subjects. Previous studies of gene expression in Alzheimer's patients have measured overall RNA levels from a section of brain tissue, but these studies don't distinguish between cell types, which can mask changes that occur in less abundant cell types, Tsai says.

 

"We wanted to know if we could distinguish whether each cell type has differential gene expression patterns between healthy and diseased brain tissue," she says. "This is the power of single-cell-level analysis: You have the resolution to really see the differences among all the different cell types in the brain."

 

Using the single-cell sequencing approach, the researchers were able to analyze not only the most abundant cell types, which include excitatory and inhibitory neurons, but also rarer, non-neuronal brain cells such as oligodendrocytes, astrocytes, and microglia. The researchers found that each of these cell types showed distinct gene expression differences in Alzheimer's patients.

 

Some of the most significant changes occurred in genes related to axon regeneration and myelination. Myelin is a fatty sheath that insulates axons, helping them to transmit electrical signals. The researchers found that in the individuals with Alzheimer's, genes related to myelination were affected in both neurons and oligodendrocytes, the cells that produce myelin.

 

Most of these cell-type-specific changes in gene expression occurred early in the development of the disease. In later stages, the researchers found that most cell types had very similar patterns of gene expression change. Specifically, most brain cells turned up genes related to stress response, programmed cell death, and the cellular machinery required to maintain protein integrity.

 

Sex differences

The researchers also discovered correlations between gene expression patterns and other measures of Alzheimer's severity such as the level of amyloid plaques and neurofibrillary tangles, as well as cognitive impairments. This allowed them to identify "modules" of genes that appear to be linked to different aspects of the disease.

 

"To identify these modules, we devised a novel strategy that involves the use of an artificial neural network and which allowed us to learn the sets of genes that are linked to the different aspects of Alzheimer's disease in a completely unbiased, data-driven fashion," Mathys says. "We anticipate that this strategy will be valuable to also identify gene modules associated with other brain disorders."

 

The most surprising finding, the researchers say, was the discovery of a dramatic difference between brain cells from male and female Alzheimer's patients. They found that excitatory neurons and other brain cells from male patients showed less pronounced gene expression changes in Alzheimer's than cells from female individuals, even though those patients did show similar symptoms, including amyloid plaques and cognitive impairments. By contrast, brain cells from female patients showed dramatically more severe gene-expression changes in Alzheimer's disease, and an expanded set of altered pathways.

 

"That's when we realized there's something very interesting going on. We were just shocked," Tsai says.

 

So far, it is unclear why this discrepancy exists. The sex difference was particularly stark in oligodendrocytes, which produce myelin, so the researchers performed an analysis of patients' white matter, which is mainly made up of myelinated axons. Using a set of MRI scans from 500 additional subjects from the Religious Orders Study group, the researchers found that female subjects with severe memory deficits had much more white matter damage than matched male subjects.

 

More study is needed to determine why men and women respond so differently to Alzheimer's disease, the researchers say, and the findings could have implications for developing and choosing treatments.

 

"There is mounting clinical and preclinical evidence of a sexual dimorphism in Alzheimer's predisposition, but no underlying mechanisms are known. Our work points to differential cellular processes involving non-neuronal myelinating cells as potentially having a role. It will be key to figure out whether these discrepancies protect or damage the brain cells only in one of the sexes -- and how to balance the response in the desired direction on the other," Davila-Velderrain says.

 

The researchers are now using mouse and human induced pluripotent stem cell models to further study some of the key cellular pathways that they identified as associated with Alzheimer's in this study, including those involved in myelination. They also plan to perform similar gene expression analyses for other forms of dementia that are related to Alzheimer's, as well as other brain disorders such as schizophrenia, bipolar disorder, psychosis, and diverse dementias. 

https://www.sciencedaily.com/releases/2019/05/190501131400.htm

Scientists propose new theory on Alzheimer's, amyloid connection

April 23, 2019

Science Daily/Florida Atlantic University

Worldwide, 50 million people are living with Alzheimer's disease and other dementias. According to the Alzheimer's Association, every 65 seconds someone in the United States develops this disease, which causes problems with memory, thinking and behavior.

 

It has been more than 100 years since Alois Alzheimer, M.D., a German psychiatrist and neuropathologist, first reported the presence of senile plaques in an Alzheimer's disease patient brain. It led to the discovery of amyloid precursor protein that produces deposits or plaques of amyloid fragments in the brain, the suspected culprit of Alzheimer's disease. Since then, amyloid precursor protein has been extensively studied because of its association with Alzheimer's disease. However, amyloid precursor protein distribution within and on neurons and its function in these cells remain unclear.

 

A team of neuroscientists led by Florida Atlantic University's Brain Institute sought to answer a fundamental question in their quest to combat Alzheimer's disease -- "Is amyloid precursor protein the mastermind behind Alzheimer's disease or is it just an accomplice?"

 

Mutations found in amyloid precursor protein have been linked to rare cases of familial Alzheimer's disease. Although scientists have gained a lot knowledge about how this protein turns into amyloid plaques, little is known about its native function in neurons. In the case of more common sporadic Alzheimer's disease, the highest genetic risk factor is a protein that is involved in cholesterol transportation and not this amyloid precursor protein. Moreover, various clinical trials designed to address Alzheimer's disease by minimizing amyloid plaque formation have failed, including one from Biogen announced last month.

 

In a study published in the journal Neurobiology of Disease, Qi Zhang, Ph.D., senior author, an investigator at the FAU Brain Institute, and an assistant research professor in FAU's Schmidt College of Medicine, along with collaborators from Vanderbilt University, tackle this Alzheimer's disease mystery by devising a multi-functional reporter for amyloid precursor protein and tracking the protein's localization and mobility using quantitative imaging with unprecedented accuracy.

 

For the study, Zhang and collaborators genetically disrupted the interaction between cholesterol and amyloid precursor protein. Surprisingly, by disengaging the two, they discovered that this manipulation not only disrupts the trafficking of amyloid precursor protein but also messes up cholesterol distribution at the neuronal surface. Neurons with an altered distribution of cholesterol exhibited swollen synapses and fragmented axons and other early signs of neurodegeneration.

 

"Our study is intriguing because we noticed a peculiar association between amyloid precursor protein and cholesterol that resides in the cell membrane of synapses, which are points of contact among neurons and the biological basis for learning and memory," said Zhang. "Amyloid precursor protein may just be one of the many accomplices partially contributing to cholesterol deficiency. Strangely, the heart and brain seem to meet again in the fight against bad cholesterol."

 

Given the broad involvement of cholesterol in almost all aspects of neurons' life, Zhang and collaborators have proposed a new theory about the amyloid precursor protein connection in Alzheimer's disease, especially in the surface of those tiny synapses, which triggers neurodegeneration.

 

"Although still in early stages, this cutting-edge research by Dr. Zhang and his collaborators at Vanderbilt University may have implications for the millions of people at risk for or suffering with Alzheimer's disease," said Randy D. Blakely, Ph.D., executive director of the FAU Brain Institute and a professor of biomedical science in FAU's Schmidt College of Medicine. "The number of people in Florida alone who are age 65 and older with Alzheimer's disease is expected to increase 41.2 percent by 2025 to a projected 720,000, highlighting the urgency of finding a medical breakthrough."

 

Locally, Alzheimer's disease affects 11.5 percent of Medicare beneficiaries in Palm Beach County and 12.7 percent of Medicare beneficiaries in Broward County (a nearly 18 percent increase over national average).

 

According to the Alzheimer's Association, Florida is number one in per capita cases of Alzheimer's disease in the U.S.

https://www.sciencedaily.com/releases/2019/04/190423113951.htm

Brain wave stimulation may improve Alzheimer's symptoms

Noninvasive treatment improves memory and reduces amyloid plaques in mice

March 14, 2019

Science Daily/Massachusetts Institute of Technology

By exposing mice to a unique combination of light and sound, neuroscientists have shown they can improve cognitive and memory impairments similar to those seen in Alzheimer's patients.

 

This noninvasive treatment, which works by inducing brain waves known as gamma oscillations, also greatly reduced the number of amyloid plaques found in the brains of these mice. Plaques were cleared in large swaths of the brain, including areas critical for cognitive functions such as learning and memory.

 

"When we combine visual and auditory stimulation for a week, we see the engagement of the prefrontal cortex and a very dramatic reduction of amyloid," says Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory and the senior author of the study.

 

Further study will be needed, she says, to determine if this type of treatment will work in human patients. The researchers have already performed some preliminary safety tests of this type of stimulation in healthy human subjects.

 

MIT graduate student Anthony Martorell and Georgia Tech graduate student Abigail Paulson are the lead authors of the study, which appears in the March 14 issue of Cell.

 

Memory improvement

 

The brain's neurons generate electrical signals that synchronize to form brain waves in several different frequency ranges. Previous studies have suggested that Alzheimer's patients have impairments of their gamma-frequency oscillations, which range from 25 to 80 hertz (cycles per second) and are believed to contribute to brain functions such as attention, perception, and memory.

 

In 2016, Tsai and her colleagues first reported the beneficial effects of restoring gamma oscillations in the brains of mice that are genetically predisposed to develop Alzheimer's symptoms. In that study, the researchers used light flickering at 40 hertz, delivered for one hour a day. They found that this treatment reduced levels of beta amyloid plaques and another Alzheimer's-related pathogenic marker, phosphorylated tau protein. The treatment also stimulated the activity of debris-clearing immune cells known as microglia.

 

In that study, the improvements generated by flickering light were limited to the visual cortex. In their new study, the researchers set out to explore whether they could reach other brain regions, such as those needed for learning and memory, using sound stimuli. They found that exposure to one hour of 40-hertz tones per day, for seven days, dramatically reduced the amount of beta amyloid in the auditory cortex (which processes sound) as well as the hippocampus, a key memory site that is located near the auditory cortex.

 

"What we have demonstrated here is that we can use a totally different sensory modality to induce gamma oscillations in the brain. And secondly, this auditory-stimulation-induced gamma can reduce amyloid and Tau pathology in not just the sensory cortex but also in the hippocampus," says Tsai, who is a founding member of MIT's Aging Brain Initiative.

 

The researchers also tested the effect of auditory stimulation on the mice's cognitive abilities. They found that after one week of treatment, the mice performed much better when navigating a maze requiring them to remember key landmarks. They were also better able to recognize objects they had previously encountered.

 

They also found that auditory treatment induced changes in not only microglia, but also the blood vessels, possibly facilitating the clearance of amyloid.

 

Dramatic effect

 

The researchers then decided to try combining the visual and auditory stimulation, and to their surprise, they found that this dual treatment had an even greater effect than either one alone. Amyloid plaques were reduced throughout a much greater portion of the brain, including the prefrontal cortex, where higher cognitive functions take place. The microglia response was also much stronger.

 

"These microglia just pile on top of one another around the plaques," Tsai says. "It's very dramatic."

 

The researchers found that if they treated the mice for one week, then waited another week to perform the tests, many of the positive effects had faded, suggesting that the treatment would need to be given continually to maintain the benefits.

 

In an ongoing study, the researchers are now analyzing how gamma oscillations affect specific brain cell types, in hopes of discovering the molecular mechanisms behind the phenomena they have observed. Tsai says she also hopes to explore why the specific frequency they use, 40 hertz, has such a profound impact.

 

The combined visual and auditory treatment has already been tested in healthy volunteers, to assess its safety, and the researchers are now beginning to enroll patients with early-stage Alzheimer's to study its possible effects on the disease.

 

The research was funded, in part, by the Robert and Renee Belfer Family Foundation, the Halis Family Foundation, the JPB Foundation, the National Institutes of Health and the MIT Aging Brain Initiative. 

https://www.sciencedaily.com/releases/2019/03/190314111004.htm

Trouble Sleeping? It May Affect Your Memory Later On

February 14, 2012

Science Daily/American Academy of Neurology

The amount and quality of sleep you get at night may affect your memory later in life, according to research that was recently released and will be presented at the American Academy of Neurology's 64th Annual Meeting in New Orleans April 21 to April 28, 2012.

 

"Disrupted sleep appears to be associated with the build-up of amyloid plaques, a hallmark marker of Alzheimer's disease, in the brains of people without memory problems," said study author Yo-El Ju, MD, with Washington University School of Medicine in St. Louis and a member of the American Academy of Neurology. "Further research is needed to determine why this is happening and whether sleep changes may predict cognitive decline."

 

Researchers tested the sleep patterns of 100 people between the ages of 45 and 80 who were free of dementia. Half of the group had a family history of Alzheimer's disease. A device was placed on the participants for two weeks to measure sleep. Sleep diaries and questionnaires were also analyzed by researchers.

 

After the study, it was discovered that 25 percent of the participants had evidence of amyloid plaques, which can appear years before the symptoms of Alzheimer's disease begin. The average time a person spent in bed during the study was about eight hours, but the average sleep time was 6.5 hours due to short awakenings in the night.

 

The study found that people who woke up more than five times per hour were more likely to have amyloid plaque build-up compared to people who didn't wake up as much. The study also found those people who slept "less efficiently" were more likely to have the markers of early stage Alzheimer's disease than those who slept more efficiently. In other words, those who spent less than 85 percent of their time in bed actually sleeping were more likely to have the markers than those who spent more than 85 percent of their time in bed actually sleeping.

 

"The association between disrupted sleep and amyloid plaques is intriguing, but the information from this study can't determine a cause-effect relationship or the direction of this relationship. We need longer-term studies, following individuals' sleep over years, to determine whether disrupted sleep leads to amyloid plaques, or whether brain changes in early Alzheimer's disease lead to changes in sleep," Ju said.

 

"Our study lays the groundwork for investigating whether manipulating sleep is a possible strategy in the prevention or slowing of Alzheimer disease."

http://www.sciencedaily.com/releases/2012/02/120214171036.htm

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