New Understanding of why ApoE4 is Associated with Alzheimer's Disease

It is by now well known that the ApoE4 variant of Apolipoprotein E is associated with a higher risk of Alzheimer's disease in many populations. This is thought to be the case because this variant is less effective in roles that influence the breakdown of amyloid-β, a form of metabolic waste that accumulates in Alzheimer's patients. Researchers here provide evidence that ApoE4 is also relevant to the harmful accumulation of damaged tau protein, another form of waste that is associated with Alzheimer's disease. This should probably be taken as an indication that greater attention should be given to the development of ways to clear tau aggregates as well as amyloid aggregates:

For decades, scientists have known that people with two copies of a gene called apolipoprotein E4 (ApoE4) are much more likely to have Alzheimer's disease at age 65 than the rest of the population. Now, researchers have identified a new connection between ApoE4 and protein build-up associated with Alzheimer's that provides a possible biochemical explanation for how extra ApoE4 causes the disease. Apolipoprotein E comes in three versions, or variants, called ApoE2, ApoE3 and ApoE4. All the ApoE proteins have the same normal function: carrying fats, cholesterols and vitamins throughout the body, including into the brain. While ApoE2 is protective and ApoE3 appears to have no effect, a mutation in ApoE4 is a well-established genetic risk factor for late-onset Alzheimer's disease. Previous reports have suggested that ApoE4 may affect how the brain clears out amyloid-β, but what was happening at the molecular level wasn't clear.

Scientists had previously uncovered hints that ApoE4 might degrade differently than the other variants, but the protein that carried out this breakdown of ApoE4 was unknown. To find the protein responsible for degrading ApoE4, researchers screened tissues for potential suspects and homed in on one enzyme called high-temperature requirement serine peptidase A1 (HtrA1). When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells - and more of the breakdown products of the protein. "There's been an idea tossed around that ApoE4 breakdown products could be toxic. Now, knowing the enzyme that breaks it down, we have a way to actually test this idea." But it's not just a lack of full-length ApoE or an increase in its fragments that may be causing Alzheimer's in people with ApoE4. Researchers also found that ApoE4 - because it binds so well to HtrA1 - keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer's.

Link: http://www.salk.edu/news-release/new-mechanism-discovered-alzheimers-risk-gene/

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