Beta Amyloid in Alzheimer's and CAA: Dr. Jekyll or Mr. Hyde?

Two weeks ago, I met with Dr. Craig Atwood at the University of Wisconsin to talk about the theory that mid-life hormonal changes trigger a chain of events leading to Alzheimer's and similar neurodegenerative diseases.  It turns out this isn't the only area in Alzheimer's research in which his thinking diverges from the mainstream.

During our discussion on reproductive hormones, I gave him Dad's autopsy report to read.

"Hmmm, severe CAA [cerebral amyloid angiopathy].  Well, I would suggest that the amyloid deposits were your dad's brain's attempt to protect itself by sealing off ruptures to prevent hemorrhage.  I don't think the amyloid caused his problems."  He opened a file cabinet and pulled out a copy of a review he wrote on this topic.  Published in Brain Research Reviews in 2003, the article lays out the logic behind the theory that amyloid [the protein found in Alzheimer's plaques and on the brain's blood vessel walls in CAA patients] could be protective, not destructive as most researchers believe.  The logic goes something like this:

• Normally, when damaged parts of the body start bleeding, the blood coagulates, or clots, and this seals off any "leakage," but can prevent blood flow through damaged vessels to neighboring tissue...
• If this happened to the blood vessel walls deep within the brain, the resulting clot would block the supply of glucose and oxygen carried by the blood to that part of the brain, depriving neurons of essential nutrients and leading to dysfunction...
• The brain has developed a different mechanism to stop bleeding:  amyloid aggregates around the blood vessel wall, sealing the lesion and preventing blood from clotting.  This allows continuous blood flow through the damaged vessel, in the way that repairing a corroded or cracked plumbing pipe would allow water to flow through the pipe...
• Amyloid has properties that make it a good sealant...
• The fact that amyloid deposits have been observed near injury sites in the brains of people who have had head trauma [see an early report, for example] can be seen as support for this theory...
• Therefore, amyloid could be a protective molecule that is formed when there is damage to the brain caused by injury, stroke, Alzheimer's or age-related changes to blood vessel walls.

Dr. Atwood is not alone in questioning whether beta amyloid is really the evil Mr. Hyde of Alzheimer's.  The Wall Street Journal summarized the larger controversy in articles published on April 9, 2004 and April 16, 2004.  But the idea that amyloid could be a vascular sealant is in direct opposition to the widely held belief that amyloid is toxic and causes Alzheimer's and brain hemorrhages like Dad's.

The theory that amyloid is a "good" protein is important in the context of researchers' and pharmaceutical companies' efforts to develop vaccines to clear amyloid from the brain.  The first clinical trial of such a vaccine in humans was halted in 2002 after some of the participants developed inflammation of the brain and spinal cord.  Despite the safety issues, the vaccine appeared to have slowed memory loss in twenty of the thirty patients followed after the trial was stopped.  Trials of vaccination against amyloid in mice have had similar results:  University of South Florida scientists report that vaccination clears amyloid plaque deposits and improves memory in mice, but increases amyloid on blood vessel walls and causes hemorrhages.

Researchers are developing new, hopefully safer, ways to vaccinate against amyloid, but Dr. Atwood remains unconvinced that these efforts will succeed.  "If you believe that amyloid is protective, then it's no surprise, that mice and humans develop problems when they are immunized," he says.

Of course, Dr. Jekyll and Mr. Hyde were one and the same.  The evil Mr. Hyde could only be suppressed if Dr. Jekyll continued to take the potion he'd developed in his lab.  Could the beta amyloid in Dad's brain have been somehow both helpful and harmful?  Maybe someday we'll have the magic potion we need to harness its good properties while suppressing the bad.

Comments

[Bailey Stewart]

Interesting information. I'm so glad you are doing this because God knows I don't have the energy and this is information that we need to know.