Stroke And Head Injury Increase Alzheimer's Risk.
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Experts suggest that 50 per cent of people over the age of 85 have AD.
US researchers have discovered that death of brain cells due to stroke or head injury could increase levels of amyloid-beta protein that help to make the senile plaques found in the brains of Alzheimer's patients and thereby raise the risk of developing the disease. Tesco and Tanzi and colleagues found that enzymes that destroy brain cells after a head injury or stroke also block the natural elimination of another enzyme that helps to make the plaque.
"We have discovered how a stroke can trigger a series of biochemical events that increase amyloid-beta production in the brain. These findings raise the prospect of novel therapies that could interfere with this process and reduce the risk of Alzheimer's disease in stroke or head trauma patients," lead author Tesco, of the MGH-MIND Genetics and Aging Research Unit said.
Scientists already knew that stroke and head injury were linked to increased risk of Alzheimer's Disease (AD), but they didn't know how. The brains of AD patients contain plaques of amyloid-beta protein, which is also toxic to brain cells. Amyloid-beta occurs when another larger protein called amyloid precursor protein (APP) is cut in half by two enzymes: beta-secretase, also known as BACE, and gamma-secretase. Usually, APP is broken down into harmless non-toxic proteins by a "friendly" enzyme called alpha-secretase.
When a brain injury occurs, such as after a stroke or head trauma, another group of enzymes called caspases go around the brain eliminating damaged brain cells. Apparently, these enzymes also encourage levels of BACE. Tesco and colleagues had already shown in previous work that BACE was normally kept within safe levels by being broken down in lysosomes, special garbage disposal compartments inside cells that digest worn out enzymes and other unwanted cellular material. BACE gets mopped up by a transporter enzyme called GGA3 that signals for it to go into the lysosomes.
When they explored this process further, they found that caspase (the enzyme that mops up damaged brain cells) also chops up GGA3 and this has two results. The obvious one is that less GGA3 is available to shepherd BACE into lysosomes for destruction, and the less obvious one is that the GGA3 fragments actively get in the way of BACE elimination. Tesco and colleagues tested this by "silencing" GGA3 in laboratory brain cells. The result was increased levels of BACE and amyloid proteins. They also found that GGA3 was broken down and BACE levels went up when they induced strokes in rats. And as a final test, they found reduced levels of GGA3, proportional to increases in BACE, in brain tissue of people with AD. Tesco and colleagues said these studies showed that: "Individuals with AD and cerebrovascular pathologies show greater cognitive impairment than those exhibiting either pathology alone. These studies indicate that there is an additive or synergistic interaction between AD and cerebrovascular pathologies."
"Furthermore, evidence is accumulating that stroke and transient ischemic attacks significantly increase the risk of AD in elderly individuals. Thus, stroke may represent either a precipitating or a triggering event in AD," they added. When these studies are taken together with other research, Tesco and colleagues suggest that repeated injury to the brain over a person's lifetime would progressively add to AD risk by "elevating cerebral A beta accumulation via BACE stabilization owing to caspase-mediated depletion of GGA3".
Alzheimer's Donation
Donate Online Now
.
Experts suggest that 50 per cent of people over the age of 85 have AD.
US researchers have discovered that death of brain cells due to stroke or head injury could increase levels of amyloid-beta protein that help to make the senile plaques found in the brains of Alzheimer's patients and thereby raise the risk of developing the disease. Tesco and Tanzi and colleagues found that enzymes that destroy brain cells after a head injury or stroke also block the natural elimination of another enzyme that helps to make the plaque.
"We have discovered how a stroke can trigger a series of biochemical events that increase amyloid-beta production in the brain. These findings raise the prospect of novel therapies that could interfere with this process and reduce the risk of Alzheimer's disease in stroke or head trauma patients," lead author Tesco, of the MGH-MIND Genetics and Aging Research Unit said.
Scientists already knew that stroke and head injury were linked to increased risk of Alzheimer's Disease (AD), but they didn't know how. The brains of AD patients contain plaques of amyloid-beta protein, which is also toxic to brain cells. Amyloid-beta occurs when another larger protein called amyloid precursor protein (APP) is cut in half by two enzymes: beta-secretase, also known as BACE, and gamma-secretase. Usually, APP is broken down into harmless non-toxic proteins by a "friendly" enzyme called alpha-secretase.
When a brain injury occurs, such as after a stroke or head trauma, another group of enzymes called caspases go around the brain eliminating damaged brain cells. Apparently, these enzymes also encourage levels of BACE. Tesco and colleagues had already shown in previous work that BACE was normally kept within safe levels by being broken down in lysosomes, special garbage disposal compartments inside cells that digest worn out enzymes and other unwanted cellular material. BACE gets mopped up by a transporter enzyme called GGA3 that signals for it to go into the lysosomes.
When they explored this process further, they found that caspase (the enzyme that mops up damaged brain cells) also chops up GGA3 and this has two results. The obvious one is that less GGA3 is available to shepherd BACE into lysosomes for destruction, and the less obvious one is that the GGA3 fragments actively get in the way of BACE elimination. Tesco and colleagues tested this by "silencing" GGA3 in laboratory brain cells. The result was increased levels of BACE and amyloid proteins. They also found that GGA3 was broken down and BACE levels went up when they induced strokes in rats. And as a final test, they found reduced levels of GGA3, proportional to increases in BACE, in brain tissue of people with AD. Tesco and colleagues said these studies showed that: "Individuals with AD and cerebrovascular pathologies show greater cognitive impairment than those exhibiting either pathology alone. These studies indicate that there is an additive or synergistic interaction between AD and cerebrovascular pathologies."
"Furthermore, evidence is accumulating that stroke and transient ischemic attacks significantly increase the risk of AD in elderly individuals. Thus, stroke may represent either a precipitating or a triggering event in AD," they added. When these studies are taken together with other research, Tesco and colleagues suggest that repeated injury to the brain over a person's lifetime would progressively add to AD risk by "elevating cerebral A beta accumulation via BACE stabilization owing to caspase-mediated depletion of GGA3".
posted by Valery Yermalitsky at
7:37 AM
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