Alzheimer's Association Archives - Sanford Burnham Prebys

Tag: Alzheimer’s Association

Institute News

Is there a type 3 diabetes?

AuthorGuest Blogger
Date

November 10, 2015

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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

The Collaboration 4 Cure Alzheimer’s research awards announced at SBP

Authorsgammon
Date

October 29, 2015

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On October 28, Mayor Kevin Faulconer, County Supervisor Diane Jacob, San Diego philanthropist Darlene Shiley, and Mary Ball, president and CEO of the Alzheimer’s Association San Diego, came to SBP to announce the recipients of research awards from San Diego’s Dementia Drug Discovery Collaborative Program, “Collaboration 4 Cure (C4C).” The awards are part of an innovative program to harvest the best research ideas toward effective treatment of Alzheimer’s disease.

Eight world-class researchers were selected by C4C to pursue promising drug discovery projects. They will be given state-of-the-art equipment, resources and expertise at SBP’s Conrad Prebys Center for Chemical Genomics (Prebys Center) and The Scripps Research Institute to search for “small molecule” chemicals that can alter changes in the brain observed in Alzheimer’s disease, potentially restoring brain health to patients.

The research award recipients and their projects include:

  • Huaxi Hu, PhD, (SBP), will search for chemicals that can activate microglia cells, which protect neurons from inflammation and remove damaged cells.
  • Elena Pasquale, PhD, (SBP), funded to search for molecules that that prevent protein aggregation that form amyloid beta plaques.
  • Lutz Tautz, PhD, (SBP), will screen for molecules that reduce levels of an enzyme thought to inhibit memory formation in Alzheimer’s patients.
  • Yunwu Zhang, PhD, (SBP), will search for compounds that target apotosin, a protein thought to damage neurons.
  • Albert La Spada, MD, PhD (UCSD), will screen for molecules that increase the activity of lysosomes, packets of enzymes with protein-clearing powers.
  • Mathew Pearn, MD, (UCSD), funded to examine protein-bearing cellular structures called endosomes from growing too large and killing neurons.
  • Subhojit Roy, PhD, (UCSD), will seek ways to separate precursor proteins from the enzymes that turn them into amyloid beta.
  • Steve L. Wagner, PhD, (UCSD), will search for a way to mute the side effects of gamma secretase inhibitors, which can disrupt the amyloid formation process.

“SBP is proud to be part of C4C. San Diego is home to some of the best neuroscientists in the world, and with our advanced screening and drug discovery capabilities at the Prebys Center, we hope to quickly advance research to prevent, treat, and even cure this terrible disease,” said Michael Jackson, PhD, senior vice president of Drug Discovery and Development at SBP.

Initial funds for the launch of C4C, totaling nearly $500,000, were obtained through the generosity of Darlene Shiley and others involved with the initiative. With a five-year funding goal of $7 million, all funds will be raised through local philanthropy, and restricted to projects from researchers at San Diego-based institutions.

Alzheimer’s disease is the third-leading cause of death in the San Diego region.

To view the KUSI newscast of the event, click here

Institute News

SBP’s 37th Annual Symposium is around the corner

Authorsgammon
Date

October 21, 2015

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This year’s Annual SBP Symposium theme is Aging and Regeneration. The line-up of distinguished speakers will cover topics from stem cell renewal, selective autophagy, and drugs that stop the aging process. Continue reading “SBP’s 37th Annual Symposium is around the corner”

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