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In mice, the antibody removes amyloid, improves vascular function without increasing the risk of cerebral haemorrhage

Monica Xiong

As you age, a normal brain protein known as amyloid beta often builds up in harmful amyloid plaques in the brain. Such plaques can be the first step on the path to Alzheimer’s disease. When they form around blood vessels in the brain, a condition known as cerebral amyloid angiopathy, the plaques also increase the risk of stroke.

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

Now researchers at the Washington University School of Medicine in St. Louis have identified an antibody that removes amyloid plaques from brain tissue and blood vessels in mice without increasing the risk of cerebral hemorrhage. The antibody targets a minor component of amyloid plaques known as apolipoprotein E (APOE).

The results, published Feb.17 in Science Translational Medicine, suggest a potentially safer approach to removing harmful amyloid plaques for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy.

“Alzheimer’s researchers have been looking for therapies that reduce amyloid in the brain for decades, and now that we have some promising candidates we are realizing that this complication exists,” said senior 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 are slightly different, but they all have this problem to a greater or lesser extent. We took a different approach by targeting APOE. It appears to be effective in removing amyloid from both brain tissue and blood vessels while avoiding this potentially dangerous side effect. “

The side effect known as ARIA in amyloid-related imaging disorders is visible in brain scans. Such abnormalities indicate swelling or bleeding of the brain caused by inflammation and can lead to headaches, confusion, and even seizures. In anti-amyloid antibody clinical trials, approximately 20% of participants develop ARIA, although not all have symptoms.

Anti-amyloid antibodies work by alerting the immune system to the presence of unwanted material – amyloid plaques – and telling the cleaning crew – inflammatory cells known as microglia – to clean up any such residue. ARIA appears to be the result of an over-excited inflammatory response. Holtzman and first author Monica Xiong, a PhD student, hypothesized that an antibody that targets only a small portion of the amyloid plaque might produce a more reluctant response that removes the plaques from both brain tissue and blood vessels, without ARIA to cause.

Fortunately, they had one such antibody on hand: an antibody called HAE-4, which targets a specific form of human APOE that is sparse in amyloid plaques and causes plaques to be removed from brain tissue. To determine whether HAE-4 also removes amyloid from cerebral blood vessels, the researchers used mice genetically engineered with human genes for amyloid and APOE4, a form of APOE that is at high risk for developing Alzheimer’s disease and cerebral amyloid angiopathy connected is. Such mice develop profuse amyloid plaques in brain tissue and cerebral blood vessels by about six months of age. In addition to Holtzman and Xiong, the research team included co-authors Hong Jiang, PhD, a senior scientist in Holtzman’s laboratory; and Gregory J. Zipfel, MD, the Ralph G. Dacey Distinguished Professor of Neurological Surgery and Head of the Department of Neurosurgery, among others.

Experiments showed that eight weeks of treatment of mice with HAE-4 reduced amyloid plaques in brain tissue and cerebral blood vessels. The treatment also significantly improved the ability of the cerebral blood vessels to expand and narrow as needed, an important sign of vascular health.

Amyloid plaques in cerebral blood vessels are dangerous because they can cause blockages or ruptures that cause strokes. The researchers compared the number of brain hemorrhages in mice treated for eight weeks with either HAE-4 or aducanumab, an anti-amyloid antibody that is in phase 3 clinical trials for Alzheimer’s disease. Due to their genetic predisposition for amyloid formation in blood vessels, the mice had a basic value for tiny cerebral hemorrhages. However, aducanumab significantly increased the number of bleeds, but HAE-4 did not.

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

“Some people get amyloid cerebral angiopathy and never get Alzheimer’s disease, but they may have strokes instead,” Holtzman said. “Amyloid build-up in cerebral blood vessels can be controlled by controlling blood pressure and other things, but there is no specific treatment for it. This study is exciting because it not only shows that we can treat the disease in an animal model, but potentially without the side effects that undermine the effectiveness of other anti-amyloid therapeutics. “

Xiong M., Jiang H., Remolina Serrano J., Gonzales ER, Wang C., Gratuze M., Hoyle R., Bien-Ly N., Silverman AP, Sullivan PM, Watts RJ, Ulrich JD, Zipfel GJ, Holtzman DM. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Scientific translational medicine. February 17, 2021. DOI: 10.1126 / scitranslmed.abd7522

This work was supported by the National Institute on Aging, grant numbers AG062027. the National Institutes of Health (NIH), grant numbers 5T32GM008151, AG047644, RF1 NS103276, and 2P30AG019610; the JPB Foundation. Imaging was performed at Washington University’s Hope Center Alafi Neuroimaging Laboratory and the Washington University Center for Cellular Imaging, partially supported by the NIH Office of Research Infrastructure Programs, Grant Number OD021629.

The 1,500 faculty physicians at Washington University School of Medicine are also medical staff at Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and is among the top 10 medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its connections with the Barnes-Jewish and St. Louis Children’s Hospitals.