Alzheimer’s Drug Permeates Blood-Brain Barrier

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Alzheimer’s disease is difficult to treat because of the blood-brain barrier (BBB), which is a membrane that is very selective in what is allowed to have contact with the brain. A team of scientists have developed a double-sided antibody that is able to hitch a ride through the BBB and then fight the enzyme responsible for the formation of plaques in the brain associated with Alzheimer’s disease. The scientists showed proof-of-concept that this treatment option could be achieved in live monkeys and mice, opening discussions for later applications in humans. The research was led by Ryan Watts from the biotech company Genentech, and the paper was published in the journal Science Translational Medicine

The BBB is the brain’s defense mechanism against potentially harmful toxins that routinely circulate through the bloodstream.  The membrane allows fresh blood, nutrients, and oxygen in, and allows waste products to flush out. Aside from these routine housekeeping molecules, not much else comes in or out.

While this is a great way to keep the brain healthy, it also makes it fairly difficult to create drugs that can pass through that barrier to treat conditions like Alzheimer’s and cancer. Trying to create openings through the BBB must be done with extreme caution. If scientists were to open it too far, it could do more harm than good by leaving it vulnerable to infection.

Watts’ team developed a double-sided antibody that binds to transferrin—a blood cell surface protein—while the other end attacks β-secretase 1 (BACE1). BACE1 is the enzyme responsible for creating amyloid-β that builds up and creates the plaque associated with Alzheimer’s. The researchers compare their approach as a chair lift going to the top of a ski slope, where the chair lift is the pathway to the BBB, and the brain is the top of the slope. The chairs keep heading up and down the hill, delivering skiers (blood cells) up to the top of the hill, past the BBB. In earlier attempts, the antibodies clung too tightly to the transferrin and did not get deposited into the brain, as well as causing negative effects on immature red blood cells. The antibody then had to be redesigned so it didn’t cling quite so tightly to the transferrin and could disassociate more easily to get to target BACE1.

In the live monkeys, the drug decreased amyloid-β levels by over 50%, without negative effects to the immature blood cells. Further studies will be needed, because the amyloid-β plaques do not cause behavior-changing disease in monkeys in exactly the same way as humans. The team hopes that not only will this development eventually be used to help treat Alzheimer’s plaques in the brain, but that a similar approach can be taken to treat other disorders and diseases in the future. 



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