Researchers from the Faculty of Medicine of the Washington University in St. Louis (USA) have identified an antibody that, in mice, removes amyloid plaques from brain tissue and blood vessels without increasing the risk of brain bleeds.
The antibody targets a component of amyloid plaques known as apolipoprotein E (APOE). Also, unlike the rest of the anti-amyloid antibodies that have successfully reduced amyloid plaques in clinical trials, this one does not cause a worrisome side effect: an increased risk of brain inflammation and bleeding.
The findings, published today in «Science Translational Medicine»Present a potentially safer approach to removing harmful amyloid plaques as a way to treat Alzheimer’s disease and cerebral amyloid angiopathy, which is caused by the accumulation of this protein around the blood vessels of the brain and which poses a risk of stroke.
For years they have been looking for therapies that reduce this protein in the brain. As the main authors explain David Holtzman y Gretchen P. Jones, his team has taken a different approach that appears to be effective in removing protein from both brain tissue and blood vessels while avoiding this side effect.
The side effect, called ARIA, is visible through brain scans and is characterized by swelling or bleeding in the brain caused by inflammation and can lead to headaches, confusion, and even seizures.
In clinical trials with other antibodies, about 20% of participants develop ARIA, although not all have symptoms.
The new antibody, HAE-4, targets only a small part of the amyloid plaque and thus causes a more restricted response that removes the plaques from both brain tissue and blood vessels without causing ARIA.
To determine whether HAE-4 also cleared amyloid protein from brain blood vessels, the researchers used mice genetically engineered with human genes for amyloid and APOE4, a form of APOE associated with a high risk of developing Alzheimer’s and cerebral amyloid angiopathy.
These mice make abundant amyloid plaques in brain tissue and blood vessels in the brain when they are about six months old.
The experiments showed, after eight weeks of treatment, HAE-4 reduced amyloid plaques in brain tissue and blood vessels in the brain.
The treatment also significantly improved the ability of the brain’s blood vessels to dilate and contract on demand, an important sign of vascular health.
The researchers compared the number of brain bleeds in mice treated for eight weekss with HAE-4 or with aducanumab, an antibody that is in phase 3 clinical trials for Alzheimer’s. But while aducanumab significantly increased the number of bleeds, HAE-4 did not.
«Some people have cerebral amyloid angiopathy and they never have Alzheimer’s dementia, but can have strokes instead, “explains Holtzman.
Although the accumulation of amyloid in the blood vessels of the brain can be controlled by managing blood pressure, there is no specific treatment for it. For Holtzman, his study “not only shows that this pathology can be treated in an animal model but it is possible that we can do it without the side effects that undermine the efficacy of other anti-amyloid therapies.”