plaques Archives - Sanford Burnham Prebys

Tag: plaques

Institute News

Study reveals how immune cells manage cholesterol levels

AuthorLindsay Ward-Kavanagh
Date

March 12, 2018

Macrophages

Atherosclerosis, the buildup of plaques inside arteries, is a key step in the development of cardiovascular disease, the leading cause of death in the United States. Elevated cholesterol levels are a risk factor for atherosclerosis, as the molecule is one of the building blocks of these plaques. However, since cholesterol is also essential in healthy cells, scientists are researching how cholesterol biology is controlled to better understand the changes that lead to disease.

Laszlo Nagy, MD, PhD, professor and director of the Genomic Control of Metabolism Program, recently collaborated with Peter Tontonoz, MD, PhD, professor, the leading senior scientist of the study and Francis and Albert Piansky Endowed Chair in Pathology and Laboratory Medicine at the UCLA David Geffen School of Medicine, to assess a network of molecules that control cholesterol transport out of macrophages, immune cells normally associated with inflammation.

“Although macrophages are usually thought of as the white blood cells that ingest invading bacteria and cleaning up cell debris after injury or infection, they can also enter a ‘alternatively activated’ state to help tissue repair and remodeling,” Nagy says. “In blood vessels, these repair state macrophages protect the body by removing cholesterol from the bloodstream. However, the accumulation of excess cholesterol in macrophages is a key event in the development of atherosclerosis. How macrophages control cholesterol transport is not well understood, but needs to be explored to better understand atherosclerosis.”

“We were interested in how macrophages are able to switch on the gene Abca1, the gene that encodes the protein that pumps cholesterol out of these cells,” Nagy explained. “We used our expertise in epigenomics to define regions of the genome that controlled the amount of Abca1 RNA produced.”

By examining long non-coding RNA strands that regulate gene expression, the study identified an RNA called MeXis that increases the expression of Abca1. Although MeXis cannot start transcription of Abca1 by itself, it does impact the ability of other proteins to transcribe the gene.

“Using our molecular tools, we were able to show that MeXis recruited another protein that helps to start transcription to Abca1, says Nagy. “Without MeXis, this protein did not interact with Abca1 and transcription was dramatically reduced, even when the cells received signals to start the process of ridding themselves of cholesterol.

“The more we understand about the biological processes that control cholesterol metabolism the better informed we are to develop strategies to prevent and treat atherosclerosis, says Nagy.  “This study reveals key insights on the regulation of Abca1, which could ultimately lead to new therapeutic approaches.”

The study was published in Nature Medicine.

Institute News

Attacking Alzheimer’s disease by controlling toxic proteins

AuthorBill Stallcup, PhD
Date

August 25, 2017

Alzheimer's disease - neurons with amyloid plaques shutterstock_111506315

The formation of amyloid-b plaques (aggregates of the amyloid-b protein) in the brain is one of the hallmarks of Alzheimer’s disease, a pathological disorder in which the death of neurons leads to dementia. Although the details involved in this process are still highly debated, many researchers agree that excessive levels of amyloid b protein (Ab for short) lie at the root of the disease. Accordingly, much research is currently focused on determining the cause of Ab build-up.

Huaxi Xu, PhD, professor and Jeanne & Gary Herberger Leadership Chair in Neuroscience at SBP, explains that, “Ab is a fragment derived from a larger protein called amyloid precursor protein (APP). The toxic Ab fragment is produced by the action of enzymes that operate inside the cell. In contrast, the action of enzymes that operate outside the cell produce a different set of non-toxic fragments of APP that are part of a normal APP recycling/replenishment system on the neuron cell surface. We wondered if we could minimize the toxic cleavage events that occur inside the cell by promoting the non-pathological, cell surface recycling of APP.”

In a recent report in the Journal of Neuroscience, the flagship journal of Society for Neuroscience, the Xu lab identified candidate molecules that might be important for promoting the cell surface recycling of APP. According to post-doctoral associate Timothy Huang, PhD, first author on the paper, “Loss of a recycling protein called SORLA has been observed in Alzheimer’s patients. Our experiments show that SORLA forms a complex with an intracellular navigational protein, SNX27, which can redirect SORLA and its binding target APP to the cell surface. On the surface, APP mostly undergoes non-pathological processing rather than generating Ab.”

Further validation of this inside versus outside concept was achieved by tweaking cellular levels of SORLA and SNX27 in cultured neurons. Increasing the levels of SORLA and SNX27 resulted in higher levels of APP on the cell surface, thus avoiding production of the toxic Ab fragment. In contrast, decreasing the levels of SORLA and SNX27 kept APP largely inside the cell, thus increasing its vulnerability to pathological cleavage.

Xu emphasizes that future work will need to aim at determining whether these SORLA-SNX27-APP interactions can be exploited in mouse models of Alzheimer’s as a means of preventing or lessening the effects of the disease.

Institute News

New potential way to slow advance of Alzheimer’s

AuthorJessica Moore
Date

July 27, 2016

Silver-stained brain tissue showing senile plaque

Like weeds taking over a garden, the brains of Alzheimer’s patients become congested with clumps of protein. These clumps arise when a peptide called amyloid beta takes a shape that sticks to other amyloid beta molecules and converts them to the same sticky form, causing a chain reaction. The sticky form of amyloid beta is toxic, so as amyloid plaques accumulate, neuronal connections, and eventually whole neurons, are lost.

Research from the laboratory of Huaxi Xu, PhD, professor in the Degenerative Diseases Program, suggests a new possible way to minimize the generation of amyloid beta and slow the advance of this tragic disease. Alzheimer’s, which affects more than 5 million people and is the 6th leading cause of death in the US, destroys patients’ memory and, at later stages, their ability to communicate and understand their surroundings.

“Our results could eventually help us discover therapeutics that address the progression of Alzheimer’s disease,” said Xu. “That would be a big step forward—no such treatment has yet been approved.”

In the new study, published in the Journal of Neuroscience, Timothy Huang, PhD, a postdoc in Xu’s lab, examined the function of a receptor called SORLA because variants of the gene encoding it had been linked to early-onset Alzheimer’s. SORLA had also been shown to affect trafficking—transport from one cellular compartment to another—of amyloid beta’s precursor. Amyloid beta is generated only in acidic compartments, where the precursor is cut to yield the toxic form, so trafficking has a big impact on how much amyloid beta is made.

“We found that SORLA, with its partner SNX27, moves the amyloid precursor protein away from the acidic compartment, where it would be cut into amyloid beta, to the cell surface,” said Huang. “There, the amyloid precursor protein is cut in a way where it cannot be cut into amyloid beta.”

“Modulating trafficking of the amyloid precursor protein through SORLA could be a new way to treat Alzheimer’s,” added Xu. “Other strategies of decreasing levels of amyloid beta, such as inhibiting the enzyme that cuts the precursor, have failed in the clinic, so new approaches are needed.”

Xu and Huang next plan to investigate whether enhancing amyloid precursor trafficking via SORLA reduces loss of neurons and improves cognitive function in an animal model of Alzheimer’s.

The paper is available online here.

Institute News

Promising target for blocking buildup of fatty plaques in arteries

AuthorJessica Moore
Date

July 22, 2016

Artery narrowed by fatty plaque

Every 34 seconds, someone in the US has a heart attack or stroke. New research from the laboratory of Erkki Ruoslahti, MD, PhD, distinguished professor in the NCI-designated Cancer Center, could lead to treatments that lower that frequency.

Heart attacks and strokes are caused by a blocked artery, which cuts off blood supply to a part of the heart or brain. These blockages occur when atherosclerotic plaques—deposits of inflamed, fat-containing cells surrounded by fibrous material inside arteries—rupture and seed blood clots. In a study published in the Journal of Controlled Release, Ruoslahti’s team shows that a specific peptide blocks expansion of these plaques at advanced stages.

“Our findings demonstrate the relevance of a new target, p32, to slowing the deposition of plaque,” said Zhi-Gang She, PhD, staff scientist in Ruoslahti’s lab and co-lead author of the paper. “We’re hopeful that drugs that act on this protein would help lower the risk for heart attacks and stroke.”

The details

The new study used a peptide called LyP-1, a ring of nine amino acids that Ruoslahti’s group has worked with for many years. LyP-1 binds to p32, a protein that’s normally located inside cells, but is found on the surface of tumor cells and active macrophages.

“Macrophages drive plaque enlargement by taking up fats and promoting inflammation, and we knew from our other investigations that LyP-1 can trigger cell death in macrophages,” explained Ruoslahti. “We thought that LyP-1 might eliminate macrophages from plaques, which would slow the advance of atherosclerosis.”

Their results confirmed this expectation—the LyP-1 peptide greatly reduced the size of plaques in mice when it was administered at advanced stages.

“Eliminating macrophages from arterial plaque is like cutting off the roots of a plant,” said She. “Not only does that get rid of a portion of the plaque, but because macrophages feed it by taking up lipids, it also keeps the plaque from getting larger.”

Clinical relevance

“The peptide itself is not a candidate drug,” added Ruoslahti. “It can only be given by injection, which isn’t practical for a chronic disease like atherosclerosis. However, we have identified small molecules that interact with p32 in a similar way to LyP-1, so they could form the basis of a drug that’s taken as a pill.”

“The key to making sure this treatment strategy is safe is confirming that it doesn’t make the plaques more likely to rupture,” commented She. “We didn’t see anything indicating that LyP-1 makes plaques less stable, but future studies should explore that issue further.”

The paper is available online here.

Institute News

Closing in on the causes of Alzheimer’s disease

AuthorGuest Blogger
Date

April 5, 2016

Header image

This post was written by Nicole Le, a guest blogger.

Imagine if we could clear the brain of plaque that accumulates and causes Alzheimer’s disease (AD) as simply as having the plaque removed from our teeth? The body has a natural clearing mechanism in place to rid the brain of these deposits, but if this mechanism gets overwhelmed or disrupted, the plaques can accumulate and lead to neurodegeneration. Continue reading “Closing in on the causes of Alzheimer’s disease”

Institute News

Researchers find protein that may create new approach to treat Alzheimer’s disease

Authorjmoore
Date

January 20, 2016

Header image

Alzheimer’s disease (AD), a common disorder that slowly destroys patients’ memory, is a highly complex disease. The condition arises when neuronal connections are lost following the accumulation of clumps of the protein beta-amyloid (called plaques) and the failure of mitochondria—the power plants within cells. Because there are many pathways that can contribute to both processes, understanding how AD progresses in all patients requires synthesizing the results of many research studies.

Continue reading “Researchers find protein that may create new approach to treat Alzheimer’s disease”

Institute News

Blocking NG2 protein may reduce atherosclerosis

Authorsgammon
Date

January 20, 2016

Header image

Researchers in the lab of William Stallcup, PhD, professor in SBP’s NCI-designated Cancer Center, in collaboration with scientists at the Institute of Basic Medical Sciences in Beijing, recently made a surprising discovery about the relationship between circulating cholesterol and the development of atherosclerosis.

Continue reading “Blocking NG2 protein may reduce atherosclerosis”

Institute News

Is there a type 3 diabetes?

AuthorGuest Blogger
Date

November 10, 2015

Header image

This article was written by guest blogger Jessica Frisch-Daiello, PhD

People with type 2 diabetes are twice as likely to develop Alzheimer’s disease—a type of dementia affecting behavior, memory, and cognitive functions. According to the Centers for Disease Control and Prevention, in 2013 Alzheimer’s ranked sixth and diabetes was seventh as the leading causes of death in the United States. Recent studies are suggesting a link between insulin resistance in the brain and Alzheimer’s disease, prompting some researchers to consider a new classification for the disease: type 3 diabetes.

People with diabetes can’t effectively break down blood sugar. Either their bodies don’t produce enough insulin (type 1 diabetes) or their bodies become desensitized to insulin (type 2 diabetes).

The exact mechanisms between insulin resistance and Alzheimer’s disease are not well understood and research is on-going. However, studies suggest that insulin resistance in the brain leads to the formation of two pathological hallmarks of Alzheimer’s disease—the formation of tau tangles and the build-up of clusters of beta amyloid peptides called plaques in the brain. The degree of insulin resistance is correlated with the amount of plaques deposited between nerve cells. Plaques create a blockade that inhibits cell-to-cell signaling in the brain. Additionally, insulin dysfunction has also been shown to affect the formation of tau tangles by mediating the activity of an important enzyme in the body, GSK-3β (glycogen synthase kinase 3).

Juan Pablo Palavicini, PhD, an SBP postdoctoral fellow in the lab of Xianlin Han, PhD, is studying the role of a particular class of molecules found in the body that might give more clues to the mechanisms connecting these two seemingly disparate diseases. According to Palavicini, “We have found that a specific lipid class called sulfatide is severely deficient in the brains of both Alzheimer’s disease patients and type 2 diabetics. Moreover, our research shows that when sulfatide is removed, there is a dramatic change in insulin levels, beta amyloid peptides, and tau tangles. We are currently exploring therapeutic techniques to restore sulfatide content as a treatment for both diseases.”

Sulfatide serves many functions in the body, including aiding neural plasticity and memory. It also plays a role in insulin secretion. A change in the expression of sulfatide has been associated with a number of conditions, including Alzheimer’s disease, Parkinson’s disease, and diabetes.

Given the association between Alzheimer’s disease and diabetes, it is important for people to incorporate healthy habits in everyday life. Both the American Diabetes Association and the Alzheimer’s Association say that daily exercise, social interaction, and a diet emphasizing fruits, vegetables, and whole grains may reduce the risk of developing, or slowing the progression of, these diseases.

Dr. Palavicini and Dr. Han are pursuing this research as part of a mentor-based postdoctoral fellowship awarded by the American Diabetes Association. This article was written by Dr. Jessica Frisch-Daiello, a postdoctoral associate in Dr. Han’s laboratory at SBP.

Institute News

Expanding the options to treat melanoma

Authorsgammon
Date

March 16, 2015

Header image

Melanoma is the most deadly form of skin cancer with approximately 10,000 deaths per year in the U.S. and more than 65,000 worldwide. Although there are more and better treatment options available today than in previous years, there is still an urgent need to develop drugs that target the numerous pathways melanoma cells use to multiply, spread, and kill. Continue reading “Expanding the options to treat melanoma”

Institute News

Why people with Down syndrome invariably develop Alzheimer’s disease

Authorsgammon
Date

October 23, 2014

Header image

A new study by researchers at Sanford-Burnham reveals the process that leads to changes in the brains of individuals with Down syndrome—the same changes that cause dementia in Alzheimer’s patients. The findings, published in Cell Reports, have important implications for the development of treatments that can prevent damage in neuronal connectivity and brain function in Down syndrome and other neurodevelopmental and neurodegenerative conditions, including Alzheimer’s disease.

Down syndrome is characterized by an extra copy of chromosome 21 and is the most common chromosome abnormality in humans. It occurs in about one per 700 babies in the United States, and is associated with a mild to moderate intellectual disability. Down syndrome is also associated with an increased risk of developing Alzheimer’s disease. By the age of 40, nearly 100 percent of all individuals with Down syndrome develop the changes in the brain associated with Alzheimer’s disease, and approximately 25 percent of people with Down syndrome show signs of Alzheimer’s-type dementia by the age of 35, and 75 percent by age 65. As the life expectancy for people with Down syndrome has increased dramatically in recent years—from 25 in 1983 to 60 today—research aimed to understand the cause of conditions that affect their quality of life are essential.

“Our goal is to understand how the extra copy of chromosome 21 and its genes cause individuals with Down syndrome to have a greatly increased risk of developing dementia,” said Huaxi Xu, PhD, professor in the Degenerative Diseases Program and senior author of the paper. “Our new study reveals how a protein called sorting nexin 27 (SNX27) regulates the generation of beta-amyloid—the main component of the detrimental amyloid plaques found in the brains of people with Down syndrome and Alzheimer’s. The findings are important because they explain how beta-amyloid levels are managed in these individuals.”

Beta-amyloid, plaques, and dementia

Xu’s team found that SNX27 regulates beta-amyloid generation. Beta-amyloid is a sticky protein that’s toxic to neurons. The combination of beta-amyloid and dead neurons form clumps in the brain called plaques. Brain plaques are a pathological hallmark of Alzheimer’s disease and are implicated in the cause of the symptoms of dementia.

“We found that SNX27 reduces beta-amyloid generation through interactions with gamma-secretase—an enzyme that cleaves the beta-amyloid precursor protein to produce beta-amyloid,” said Xin Wang, PhD, a postdoctoral fellow in Xu’s lab and first author of the publication. “When SNX27 interacts with gamma-secretase, the enzyme becomes disabled and cannot produce beta-amyloid. Lower levels of SNX27 lead to increased levels of functional gamma-secretase that in turn lead to increased levels of beta-amyloid.”

SNX27’s role in brain function

Previously, Xu and colleagues found that SNX27-deficient mice shared some characteristics with Down syndrome, and that humans with Down syndrome have significantly lower levels of SNX27. In the brain, SNX27 maintains certain receptors on the cell surface—receptors that are necessary for neurons to fire properly. When levels of SNX27 are reduced, neuron activity is impaired, causing problems with learning and memory. Importantly, the research team found that by adding new copies of the SNX27 gene to the  brains of Down syndrome mice, they could repair the memory deficit in the mice.

The researchers went on to reveal how lower levels of SNX27 in Down syndrome are the result of an extra copy of an RNA molecule encoded by chromosome 21 called miRNA-155. miRNA-155 is a small piece of genetic material that doesn’t code for protein, but instead influences the production of SNX27.

With the current study, researchers can piece the entire process together—the extra copy of chromosome 21 causes elevated levels of miRNA-155 that in turn lead to reduced levels of SNX27. Reduced levels of SNX27 lead to an increase in the amount of active gamma-secretase causing an increase in the production of beta-amyloid and the plaques observed in affected individuals.

“We have defined a rather complex mechanism that explains how SNX27 levels indirectly lead to beta-amyloid,” said Xu. “While there may be many factors that contribute to Alzheimer’s characteristics in Down syndrome, our study supports an approach of inhibiting gamma-secretase as a means to prevent the amyloid plaques in the brain found in Down syndrome and Alzheimer’s.”

“Our next step is to develop and implement a screening test to identify molecules that can reduce the levels of miRNA-155 and hence restore the level of SNX27, and find molecules that can enhance the interaction between SNX27 and gamma-secretase. We are working with the Conrad Prebys Center for Chemical Genomics at Sanford-Burnham to achieve this,” added Xu.

#  #  #

 This research was supported in part by US NIH/National Cancer Institute Grant AG038710, AG021173, NS046673, AG030197 and AG044420, and grants from the Alzheimer’s Association, the Global Down Syndrome Foundation, the BrightFocus Foundation (formerly the American Health Assistance Foundation) and the National Natural Science Foundation of China.

To link to the paper click: http://www.cell.com/cell-reports/abstract/S2211-1247(14)00820-1