December 1, 2023

Cornell Researchers Determine Amyloid Beta Interactions Associated with Alzheimer’s Disease and Cerebral Amyloid Angiopathy

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Weill Cornell Medicine researchers gave new insights on the onset of Alzheimer’s disease and a cerebrovascular disorder known as cerebral amyloid angiopathy, identifying the mechanisms of the protein amyloid beta in an Oct. 3 study.

Although the extensive role of amyloid beta in brain function is currently unknown, it is typically produced in normal neural activity and removed by blood vessels in the brain. However, in patients with Alzheimer’s and CAA — the accumulation of amyloid beta in cerebral blood vessels — amyloid beta is known to build up in the brain, which can lead to neurovascular damage, cognitive impairment and inflammation and hemorrhage in the brain. 

According to senior author and Director of the Feil Family Brain and Mind Research Institute Prof. Costantino Iadecola, neurology, amyloid beta accumulation is due to neurovascular dysfunction, meaning blood vessels in the brain are no longer able to maintain blood flow and dispose of amyloid beta. 

Iadecola and his team further discovered that loss of neurovascular function is due to interactions between amyloid beta and immune cells known as border-associated macrophages. Amyloid beta binds to receptors called CD63 in BAM that paralyze blood vessels, restricting blood flow and preventing amyloid beta removal from the brain. 

These macrophages are proposed to typically arise in the brain very early in development — during embryogenesis or the first eight weeks of development after fertilization — and remain there. Thus, the effects of amyloid beta binding to these cells cause blood vessel paralysis that can be long-lasting, according to Iadecola. 

However, co-author Prof. Laibaik Park, neuroscience, shared that bone marrow transplants that replace normal BAM in preclinical models with Alzheimer’s and CAA with BAM without CD63 receptors, resulting in better blood circulation in the brain and cognitive function in the models.

“If you replace border-associated macrophages with ones lacking CD36 receptors, amyloid beta would not be able to induce production of reactive oxidative species,” Park said. “This prevents universal dysfunction and is also associated with protection of neurovascular function and prevention of cognitive impairment.” 

These findings have applications for medicine, as CD36 could become a potential target to remove for treatment of Alzheimer’s and other diseases associated with amyloid beta accumulation. According to Iadecola, because BAM are typically located near blood vessels of the brain, drug administration may be relatively accessible.

“There are a diversity of approaches that could be used to selectively target border-associated macrophages,” Iadecola said. “The good thing about these cells is that they are near the blood vessels, so the drug doesn’t have to go very far. At the moment, there is no way to target them specifically, so it will be the next research topic to explore.” 

Targeting CD36 in BAM may provide a solution for amyloid-related imaging abnormalities, which are reactions to antibody treatments used to treat mild cognitive impairment and Alzheimer’s disease. Patients experiencing ARIA present with brain edema, swelling that occurs due to an accumulation of excess fluid in the brain tissues, and hemorrhage. However, reducing these symptoms may allow them to continue their treatment. 

The team has several next steps in regards to their recent research. According to Park, bone marrow transplantation utilized to create BAM lacking CD36 requires exposure of radiation to the brain and produces side effects in mouse models. Thus, the team is working on deleting the BAM CD36 gene in mouse lines to further determine its role in cerebral amyloid angiopathy. 

Iadecola explained that the research team is additionally interested in studying Apolipoprotein E., a protein involved in fat metabolism and also associated with Alzheimer’s disease, in relation to BAM and its potential role in amyloid beta clearance. 

“Hopefully, our work is going to provide that fundamental knowledge that can be used to bring treatments to patients,” Iadecola said. “Because that’s ultimately what we’re interested in. We want to treat our patients.” 

Kaitlyn Lee can be reached at [email protected].