Researchers at Weill Cornell Medicine have made a significant discovery regarding the role of amyloid beta, a peptide linked to Alzheimer’s disease, in damaging blood vessels and causing neurodegeneration.
Their findings, published in Molecular Neurodegeneration on October 3rd, shed light on the mechanisms underlying cognitive decline in Alzheimer’s and related conditions such as cerebral amyloid angiopathy (CAA), providing potential insights for future treatments.
Understanding Amyloid Beta Accumulation
Amyloid beta is a normal byproduct of brain function. However, in conditions like Alzheimer’s and CAA, these molecules accumulate and harm the walls of blood vessels in the brain.
This vascular damage can lead to brain bleeds and cognitive impairment. Until now, the exact mechanism behind this process remained unclear.
The Role of Border-Associated Macrophages
Previous studies had shown that immune cells called border-associated macrophages, which surround brain blood vessels, possess CD36 receptors on their surfaces capable of binding to amyloid beta.
This research discovered that amyloid beta activates CD36 receptors, prompting the release of oxygen free radicals, known to damage arterial walls and disrupt essential blood flow in the brain.
Dr. Costantino Iadecola’s Insights
Dr. Costantino Iadecola, the senior author of the study, explained that the brain typically efficiently removes amyloid beta to maintain its health.
However, when amyloid beta accumulates, it triggers a response from border-associated macrophages, causing the release of harmful free radicals. These free radicals, in turn, impair blood vessels in the brain.
The study demonstrated that free radicals from amyloid beta-induced CD36 activation can paralyze blood vessels in the brain.
This leads to the accumulation of amyloid beta in the smooth muscle of vessel walls, further obstructing blood flow and ultimately resulting in cerebral amyloid angiopathy (CAA) and cognitive impairment.
To validate their findings, the researchers eliminated CD36 receptors in the border-associated macrophages of a preclinical Alzheimer’s disease model with CAA and cognitive impairment.
This intervention yielded promising results, as it improved vascular function, reduced amyloid beta buildup around blood vessels, and enhanced cognitive function in the mice.
Furthermore, without CD36, macrophages produced fewer reactive oxygen radicals, mitigating oxidative stress, improving neurovascular function, and promoting the clearance of amyloid beta from the brain.
Potential Implications for Alzheimer’s Treatment
The study’s findings suggest that targeting CD36 receptors in border-associated macrophages may hold therapeutic potential for conditions associated with amyloid accumulation in blood vessels.
One potential application is addressing amyloid-related imaging abnormalities (ARIA), a concerning side effect of monoclonal antibody drugs like aducanumab used in Alzheimer’s treatment.
In some patients receiving high-dose amyloid beta immunotherapy, brain edema or hemorrhages occur, necessitating treatment discontinuation.
Modifying CD36 in brain macrophages may offer a solution to counteract ARIA and enhance the effectiveness of amyloid beta immunotherapy.
Conclusion
The research conducted at Weill Cornell Medicine provides valuable insights into the role of amyloid beta and CD36 receptors in neurodegeneration and cognitive decline.
By understanding these mechanisms, future treatments for Alzheimer’s and related conditions may be developed, offering hope for improved patient outcomes and potentially reducing the impact of debilitating diseases.
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The research findings can be found in Molecular Neurodegeneration.
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