Huaxi Xu Archives - Sanford Burnham Prebys

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Institute News

Top neuroscientists gather at Sanford Burnham Prebys’ annual symposium

AuthorMonica May
Date

November 18, 2019

Symposium organizers Jerold Chun (fourth from right), Randal Kaufman (second from left), Barbara Ranscht (third from right) and Huaxi Xu (far left), pose with the speakers

A mother who no longer remembers her son. A daughter who took doctor-prescribed pain medication and slipped into addiction. A father who has trouble grasping a pen and eventually becomes unable to walk. Neurological disorders are some of the most painful and complex conditions our society faces today. Yet much about the brain remains unknown, hindering our ability to help people with these disorders.

To help shed light on the brain’s mysteries, on November 1, 2019, more than 250 neuroscientists gathered at Sanford Burnham Prebys’ one-day symposium to share their latest discoveries. Organized by professors Jerold Chun, MD, PhD; Randal Kaufman, PhD; Barbara Ranscht, PhD; and Huaxi Xu, PhD, the event attracted scientists from around the world eager to learn more about biological clues that are leading to effective therapies. Read the full list of the invited speakers and their talks.

“Nearly every day we read about the toll neurological diseases such as Alzheimer’s, dementia, mental health disorders and more take on our society,” said Kristiina Vuori, MD, PhD, president of Sanford Burnham Prebys, in her introductory address. “Our symposium brings together scientists at the frontiers of brain research who share their latest discoveries to open new paths toward new and better treatments.”

More than 50 million Americans are affected by neurological disorders, including Alzheimer’s disease, dementia, addiction and more, according to the National Institute of Neurological Disorders and Stroke. Most of these conditions are not well addressed by current medicines.

At the symposium, world-renowned scientists from Stanford University, Mount Sinai, University of Vienna and other top-tier institutes gave talks describing their strategies to uncover the molecular basis of brain disorders and how these discoveries are advancing potential therapies. A national plan to address Alzheimer’s and other dementia types was described by Eliezer Masliah, MD, the National Institute of Aging’s director of the Division of Neuroscience.

“This was my first scientific conference, and it was perfect for learning about a wide range of cutting-edge brain research,” said attendee Jaclyn Beck, a PhD student at UC Irvine who studies the role of the brain’s immune cells, called microglia, in Alzheimer’s disease. “I have several pages of notes from the talks detailing findings I want to investigate and people I want to contact.”

For the past 40 years, our Institute has invited leading experts on one scientific topic to share their latest research at an annual symposium. By encouraging connection and collaboration, we hope to inspire insights that improve human health. The 41st annual symposium will take place in November 2020 and focus on the biology of organelles, specialized pouches within cells that carry out critical functions such as generating power and breaking down waste, and its role in health and disease.

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.

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

Authorjmoore
Date

January 20, 2016

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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

Happy Holidays from Sanford-Burnham!

Authorpbartosch
Date

December 23, 2014

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As the year draws to a close, we look back on Sanford-Burnham’s many achievements in 2014. Over the year, our scientists published numerous papers in high-profile journals; secured significant grant funding; partnered with companies, institutes, and nonprofit organizations from across the country and the globe; and they took important steps toward our ultimate goal – to have a tangible impact on human health. Here are 14 accomplishments of 2014 that we are proud to share with you: Continue reading “Happy Holidays from Sanford-Burnham!”

Institute News

Why people with Down syndrome invariably develop Alzheimer’s disease

Authorsgammon
Date

October 23, 2014

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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.

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 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