As scientists struggle to find an effective way to prevent Alzheimer’s disease, researchers at the University of Wisconsin-Madison may have found a new approach to interrupting the process that leads to the devastating disease.
Building on their knowledge of two enzymes that control an “uber” enzyme critical to the development of the disease, the scientists found that the two enzymes are present in the brains of Alzheimer’s patients. And by screening some 15,000 compounds, they discovered two that lower activity of the enzymes in test tubes.
The research, published in the Jan. 20 issue of The Journal of Biological Chemistry, offers hope for a novel approach to preventing Alzheimer’s disease (AD). No other research team has focused on the two enzymes and the way they affect the uber enzyme.
More than five million people in the United State may have Alzheimer’s, a complicated disease that has been a challenge to understand. Many researchers have zeroed in on amyloid, which accumulates in the brains of patients with Alzheimer’s, as one of the main culprits.
Amyloid originates from a protein called amyloid precursor protein, or APP. An enzyme called beta-site APP cleaving enzyme, or BACE1, cuts APP to produce amyloid and another small fragment called AICD. Both amyloid and AICD are toxic to nerve cells and have been linked to AD.
The current research, under the direction of Dr. Luigi Puglielli, associate professor of medicine at the UW School of Medicine and Public Health (SMPH), centers generally on BACE1. Elevated levels of this enzyme, which rise normally during aging, may lead to high levels of amyloid.
The 6 pillars of a brain-healthy lifestyle
The health of your brain, like the health of your body, depends on many factors.
While some factors, such as your genes, are out of your control, many powerful lifestyle factors are within your sphere of influence.
The six pillars of a brain-healthy lifestyle are:
– Regular exercise
– Healthy diet
– Mental stimulation
– Quality sleep
– Stress management
– An active social life
The more you strengthen each of the six pillars in your daily life, the healthier and hardier your brain will be.
When you lead a brain-healthy lifestyle, your brain will stay working stronger… longer.
“The prediction is that if you prevent the up-regulation of BACE1 caused by aging, you could prevent the increased risk of Alzheimer’s disease that is also associated with aging,” says Puglielli, of the Geriatric Research and Education Center at the William S. Middleton Memorial Veterans Hospital in Madison.
Drugs to block BACE1 could, in theory, prevent the build-up of amyloid and help slow or stop the disease. A handful of companies are devoting resources to finding various ways to block BACE1; the Wisconsin Alumni Research Foundation (WARF) has filed a patent for the compounds Puglielli has discovered to be effective.
Is there a way to prevent Alzheimer’s disease? Last week, a study presented at the Alzheimer’s Association International Conference in Paris suggested there might be, something that would give hope to millions who worry that one day they may be struggling with dementia.
The new study, by researchers at the University of California, San Francisco, estimated how many Alzheimer’s cases might be attributable to certain behaviors or conditions: physical inactivity, smoking, depression, low education, hypertension, obesity and diabetes.
The authors used a mathematical model to surmise that these behaviors and conditions, all of which can be modified, are responsible for about half of the roughly 5.3 million Alzheimer’s cases in the United States and 34 million cases worldwide.
And they calculated that if people addressed these risks – by exercising, quitting smoking, increasing their education or losing weight, for example – a significant number of Alzheimer’s cases could be prevented. Reducing the prevalence of these risk factors by 10 percent, the researchers estimated, could prevent 1.1 million cases worldwide; reducing these risk factors by 25 percent could prevent more than three million cases.
For the treatment of moderate pain or moderately severe pain including arthralgia, headache, myalgia, dental pain following oral surgery such as extraction of impacted molars or chronic conditions such as low-back pain, bone pain and cancer-related pain.
Maximum Dosage Limits:
- Adults: 100 mg/dose PO or 400 mg/day PO.
- Elderly >= 75 years: 100 mg/dose PO or 300 mg/day PO.
- Elderly 65 – 74 years: 100 mg/dose PO or 400 mg/day PO.
- Adolescents >= 16 years: 100 mg/dose PO or 400 mg/day PO.
- Adolescents 13 – 15 years: Maximum dosage has not been determined.
- Children: Maximum dosage has not been determined.
In 2007, Puglielli and his colleagues discovered that regulation of BACE1 occurs when it undergoes a molecular process called acetylation, which changes its structure. If BACE1 is acetylated, it can travel through the cell in a series of steps to produce the amyloid precursor. If it isn’t acetylated, it takes another path toward degradation.
The SMPH team set out to find what makes the acetylation occur, and in 2009 found that two enzymes-ATase1 and ATase2-are responsible.
What Causes Alzheimer’s Disease
Stressed Out? Your Brain Feels the Pain
Cortisol and adrenaline are naturally produced by your body’s adrenal glands in response to stressful situations. At their best, they allow you to respond to the increased stress in appropriate ways.
Typically, when the stress is over, levels of both these hormones return to normal. Their purpose has been served and no long-term harm is done to your body or brain. However, for individuals who experience chronic stress this does not happen… cortisol levels stay high and the consequences for your brain health can be disastrous.
For example, when it is exposed to continued high levels of cortisol, your brain can actually be prevented from taking up the full glucose it needs to function and thrive properly. Excess and continued exposure to cortisol can also slow your nerve impulse transmissions. Eventually, the result is that previously healthy brain cells will die.
In addition, when we look at how cortisol affects your hippocampus, we see even more troubling signs of damage. The hippocampus is the part of your brain that helps sort and store your memories. Studies have shown that the size of hippocampus in Alzheimer’s patients is considerably reduced and therefore, as you can imagine, its function is likewise slowed.
As the disease progresses, increased cortisol also inhibits a process called “long-term potentiation” that is critical in helping you lay down your memories in ways that are permanent, logical, and accessible.
In other words, high levels of cortisol can be lethal to your brain neurons.
It can also seriously impair your memory itself, because the hormones actually attack your brain at the source of its memory storage and sorting. But cortisol is just one part of the equation. Let’s see how free radicals can contribute to the onset and progression of the disease.
In the current paper, the researchers found that both ATase1 and ATase2 are expressed in neurons and glial cells. The enzymes are also up-regulated in the brains of AD patients. The researchers looked for compounds that could shut down ATase1 and ATase2, creating an assay to measure the enzyme levels in test tubes so they could screen about 15,000 compounds. The experiments showed that 186 compounds could do the trick.
The scientists then introduced the compounds into several kinds of cellular systems to see if they could reach ATase1 and ATase2 inside the cells.
“We ended up with two compounds that could affect the enzymes in living cells-compound 9 and compound 19,” Puglielli says.
Analyzing the biochemistry and cell biology of the compounds, the scientists found that they shut down ATase1 and 2, which in turn resulted in less acetylation of BACE1-and therefore less production of the amyloid precursor protein.
The UW scientists are now testing the compounds in an animal model of AD. Preliminary results are encouraging.
Simple ways to connect with your partner, family member, or friend
Commit to spending quality time together on a regular basis. Even during very busy and stressful times, a few minutes of really sharing and connecting can help keep bonds strong.
Find something that you enjoy doing together, whether it is a shared hobby, dance class, daily walk, or sitting over a cup of coffee in the morning.
Try something new together. Doing new things together can be a fun way to connect and keep things interesting. It can be as simple as trying a new restaurant or going on a day trip to a place you’ve never been before.
“Alzheimer’s is a complex disease, but finding compounds that affect BACE1 through these two enzymes gives us hope that we are making progress with a novel approach to preventing the disease,” Puglielli says.
Source: University of Wisconsin-Madison