Researchers identify an antibody that removes amyloid plaques without the risk of brain milk

As people age, a normal brain protein called amyloid beta often begins to accumulate into harmful amyloid plaques in the brain. Such records can be the first step on the path to Alzheimer’s depression. When they form around blood vessels in the brain, a condition known as amyloid cerebral angiopathy, the plaques also raise the risk of strokes.

Several antibodies targeting amyloid plaques have been studied as experimental treatments for Alzheimer’s disease. Such antibodies may treat amyloid cerebral angiopathy, although they have not yet been evaluated in clinical trials. But all of the anti-amyloid antibodies that have successfully reduced amyloid plaques in Alzheimer’s clinical trials may also have a worrying side effect: an increased risk of brain sloughing and inflammation.

Now, researchers at the University of Washington School of Medicine in St. Louis has identified an antibody that, in mice, removes amyloid plaques from brain tumors and blood vessels without increasing the risk of cerebral edema. The antibody targets a small portion of an amyloid plaque called apolipoprotein E (APOE).

The conclusions, published on 17 February in Science Translational Medicine, suggested a potentially safer approach to eradicating harmful amyloid plaques as a way to treat Alzheimer’s disease and amyloid cerebral angiopathy.

“Alzheimer’s researchers have been searching for decades for treatments that reduce amyloid in the brain, and now that we have some promising candidates, we are discovering that this problem exists,” he said. lead author David Holtzman, MD, Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology.

“Each of the antibodies that remove amyloid plaques in clinical trials is slightly different, but they all have this problem, to a greater or lesser extent. We have taken a different approach with targeting APOE, which appears to be effective in removing amyloid from both the brain and blood vessels, while at the same time avoiding this side effect. could be dangerous. “

The side effect, known as ARIA, for amyloid-related image atrophy, can be seen on brain scans. Such anomalies indicate inflammation or inflammation of the brain caused by inflammation, which can lead to headaches, confusion and even seizures. In clinical trials for anti-amyloid antibodies, about 20% of participants develop ARIA, although not all of them have symptoms.

Anti-amyloid antibodies work by alerting the immune system that unwanted substances -; amyloid plaques -; and leading the cleaning team -; inflammatory cells called microglia -; to clean up that debris. ARIA appears to be the result of an overenthusiastic inflammatory response. Holtzman and first-time author Monica Xiong, a graduate student, suspected that an antibody targeting just a small portion of the amyloid block could detect a narrower response that clears the plaques from both brain and blood vessels without caused by ARIA.

Fortunately, they had one such antibody at hand: an antibody called HAE-4 that targets a specific form of human APOE that is rarely found in amyloid plaques and stimulates the removal of plaques from brain tissue. To determine whether HAE-4 also removes amyloid from brain blood vessels, the researchers used genetically modified mice of human genes for amyloid and APOE4, a type of risk-related APOE high for developing Alzheimer’s and cerebral amyloid angiopathy.

Mice like this develop abundant amyloid plaques in brain tissue and brain blood vessels before they are about six months old. Along with Holtzman and Xiong, the research team included co-authors Hong Jiang, PhD, senior scientist in Holtzman’s laboratory, and Gregory J. Zipfel, MD, Distinguished Professor Ralph G. Dacey in neurological surgery and head of the Department of Neurosurgery, among others.

Tests showed that eight weeks of treatment of mice with HAE-4 reduced amyloid plaques in brain tissue and cerebral blood vessels. Treatment also significantly improved the ability of brain blood vessels to shrink and limit demand, an important indicator of biological health.

Amyloid plaques in cerebral blood vessels are dangerous because they can lead to obstruction or spinal cord injury that causes strokes. The researchers compared the number of brain strokes in mice treated for eight weeks with HAE-4 or aducanumab, an anti-amyloid antibody that is in phase 3 clinical trials for Alzheimer’s. The mice had a baseline level of tiny brain pulses due to their genetic prediction for amyloid buildup in blood vessels. But aducanumab significantly increased the number of strokes while HAE-4 did not.

Further study showed that HAE-4 and aducanumab initially had immune responses against amyloid plaques that were similar in potency. However, mice treated with the anti-APOE antibody resolved the inflammation within two months, while inflammation persisted in mice treated with the anti-amyloid antibody.

Some people get amyloid cerebral angiopathy and never get Alzheimer’s depression, but they may have strokes instead. The buildup of amyloid in blood vessels of the brain can be controlled by controlling blood pressure and other things, but there is no specific treatment for it. This study is encouraging because it shows that not only can we treat the condition in an animal model, but we may be able to do without the side effects that weaken the effectiveness of treatment. other anti-amyloid. “

David Holtzman, MD, Washington University School of Medicine, St. Louis