Source: Thailand Medical Dec 12, 2019 4 years, 11 months, 1 week, 5 days, 1 hour, 16 minutes ago
560 million people or 8% of the world population comprising mostly of
East Asians from countries like China, Korea, Taiwan, Japan and Hong Kong are at a higher risk of developing
Alzheimer due to a presence of a mutated gene. The risk is even aggravated by
alcohol consumption.
According to a new study by researchers at the Stanford University School of Medicine, a common mutation in a key enzyme involved in
alcohol metabolism increases damage in cells from patients with Alzheimer's disease and in mice.
The mutation in
aldehyde dehydrogenase 2, or ALDH2, is typically associated with facial redness following alcohol consumption. It causes the activity of the enzyme to be greatly reduced, resulting in the buildup of acetaldehyde, a toxic product of alcohol metabolism. The body responds to the presence of the toxin with skin flushing and inflammation.
The mutation is prevalent in the
East Asian population. The flushing response to
alcohol among people who carry the mutation is sometimes called "
Asian glow."
Dr Daria Mochly-Rosen, Ph.D., professor of chemical and systems biology said that understanding the relationship of
alcohol and genes linked to
Alzheimer's disease will have broad consequences, she said, since a large group of people may unknowingly be harming their future health by regularly consuming alcohol.
Dr Mochly-Rosen told
Thailand Medical News, "Our data suggest that
alcohol and
Alzheimer's disease-prone genes may put humans at greater risk of
Alzheimer's onset and progression. This is based on our patient-derived cell studies and our animal studies, so an epidemiological study in humans should be carried out in the future."
Dr Mochly-Rosen, who holds the George D. Smith Professorship in Translational Medicine, is the senior author of the study, which will be published Dec. 12 in
Acta Neuropathologica Communications. The lead author is postdoctoral scholar Dr Amit Joshi, Ph.D.
Previous epidemiological studies in
East Asian populations have suggested an association between the mutation in
ALDH2 that causes facial flushing and
Alzheimer's disease. However, there have also been other studies that didn't find an association. To further explore a possible role for
ALDH2, the authors of the current study examined cell cultures made using cells from 20 patients with
Alzheimer's disease. One culture had the
ALDH2 mutation, also known as ALDH2*2. While the amount of ALDH2*2 protein in this sample matched the level of
ALDH2 protein in normal cells, the mutant protein had only a fraction of the ability to break down acetaldehyde.
When compared to normal cells, the ALDH2*2 cells had more free radicals and more 4-HNE, anot
her toxic chemical that's normally processed by
ALDH2.
Dr Mochly-Rosen added, "Free radicals are formed when we have fever, when we have chronic diseases, when we are stressed; free radicals are formed under many kinds of pathological stimuli. These free radicals form toxic aldehydes, and the job of
ALDH2 is to remove these toxic chemicals. Once these aldehydes accumulate, the first organelles that they damage are the organelles that contain the enzyme that is supposed to get rid of them: the mitochondria. This vicious cycle ultimately leads to reduced mitochondrial activity, increased free radical formation by the damaged mitochondria and, in the case of
Alzheimer's disease, to death of neurons.”
The level of free radicals was restored to normal following the addition of Alda-1, a small molecule that "fixes" ALDH2*2 by binding to the catalytic site and restoring the enzyme to a functional structure.
Dr Mochly-Rosen and her colleagues discovered Alda-1 as an activator of ALDH2*2 in 2008. Alda-1 also activates the nonmutant
ALDH2 and therefore may benefit more people, she said. Clinical trials are in progress to test the usefulness of Alda-1-like molecules as a treatment for a variety of health conditions. Mochly-Rosen consults for these clinical trials but does not own stocks in the pharmaceutical company conducting the them. The company did not fund any of the current research.
Upon adding
alcohol to cells with either
ALDH2 or ALDH2*2 derived from patients with
Alzheimer's disease led to an increase in free radicals; the effect was greater, though, in the ALDH2*2 cells. Alda-1 reversed these effects, though not completely. These results indicate that
alcohol damages cells normally protected by
ALDH2 and that this damage is more severe in cells from patients with a genetic form of
Alzheimer's disease, the study reports.
To extend the research further understand the link between
alcohol and
ALDH2, the researchers studied mice that carry ALDH2*2. The mice were injected with
alcohol each day for 11 weeks to simulate chronic
alcohol use.
Dr Joshi commented, "The animals were given one gram per kilogram per day, which is equivalent to about four to five drinks for the animal. But since mice metabolize
alcohol much faster than humans, it comes to about two drinks a day."
Similar to cell cultures, the researchers saw that mice with the ALDH2*2 gene produced more free radicals than normal mice when provided with
alcohol. The mutant mice also accumulated beta-amyloid protein fragments and activated tau protein more than normal mice. Both of these changes are molecular signatures for
Alzheimer's disease. Treatment with Alda-1 reduced the accumulation of both of these toxic proteins.
Also, the ALDH2*2 mice showed an increase in neuroinflammatory signs following their injection with
alcohol compared with normal mice. Neuroinflammation, or inflammation of the nervous system, is normally caused by injury, infection and even the aging process, but recent studies have found that chronic neuroinflammation worsens the progression of neurodegenerative diseases, such as
Alzheimer's disease. Treatment with Alda-1 reduced the accumulation of these neuroinflammatory proteins in mice.
The medical researchers also prepared cell cultures from the brains of normal and ALDH2*2 mice and found that
alcohol led to increased levels of free radicals and cell-death proteins not only in neurons, but in astrocytes, as well. Astrocytes are cells found in the central nervous system that provide support for neuronal function and maintenance, but that can also contribute to neuroinflammation. Treatment with Alda-1 reduced the
alcohol-induced changes in the cell cultures, the study found.
The study findings point to a previously undiscovered role of
alcohol and
ALDH2 in
Alzheimer's disease. Since the work was done in cell cultures and mice, further validation is needed in large epidemiological studies of humans to see whether
alcohol drinkers who have the ALDH2*2 mutation develop
Alzheimer's disease at a higher-than-average rate, Dr Mochly-Rosen said. Such studies could help determine whether decreased
alcohol consumption and treatment with compounds, such as Alda-1, might reduce the progression and burden of
Alzheimer's disease in the world's aging population.
Further to this, there have also been other studies demonstrating that ALDH2*2 increases the risk of developing cancer in the esophagus. Because
ALDH2 is so important for human health, Che-Hong Chen, a senior research scientist in the Mochly-Rosen Lab, organized the Stanford-Taiwan
ALDH2 Deficiency Research Consortium, or STAR. This group aims to promote research and public awareness about the
ALDH2 mutation in
East Asia, where nearly half the population carries it.
Dr Mochly-Rosen concluded, “Alda-1-like compounds may prove to aid in treatment to reduce the risk of
Alzheimer's disease in humans.”