Amyloid peptides are harmful to the blood vessels that supply the brain with blood in Alzheimer's disease—thus accelerating cognitive decline by limiting delivery of oxygen-rich blood and nutrients, according to new research. In their animal studies, study investigators reveal how amyloid-β accumulates in blood vessels and how such accumulation and damage might be ultimately prevented, according to research published online in Proceedings of the National Academy of Sciences.
The researchers said this study is the first to identify the role that the innate immunity receptor CD36 plays in damaging cerebral blood vessels and promoting the accumulation of amyloid deposits in these vessels, a condition known as cerebral amyloid angiopathy (CAA). Practical Neurology asked one of the study authors, Costantino Iadecola, MD, a Professor of Neurology at Weill Cornell Medical College and director of the new Brain and Mind Research Institute at Weill Cornell Medical College, to discuss the findings.
What did your study reveal and how does it compare to what we knew about amyloid peptides and cerebral blood vessels? What should neurologists take away?
It has been known for years that the A-beta peptide accumulates in cerebral blood vessels (Cerebral amyloid angiopathy or CAA). However, two main questions remained open. First, the factors driving the accumulation were not known. Second, it remained unclear whether CAA was involved at all in the brain dysfunction underlying the dementia in Alzheimer's disease. Our study helped address these outstanding questions in a mouse model of A-beta accumulation (Tg2576 mouse). We found that CD36 is involved in the development of CAA, and that such involvement is related to preservations of the structural and functional integrity of cerebral blood vessels. Therefore, keeping the vessels healthy and functional dampened the accumulation of A-beta in cerebral arterioles. Furthermore, we found that suppressing CAA and improving vascular function was sufficient to improve the cognitive deficits that the mice developed over time, even though the deposition of A-beta in the brain parenchyma (amyloid plaques) was still present. Therefore, improving CAA is able to improve cognition despite massive accumulation of amyloid plaques.
What did we know about CD36 before your study? Why was it an intriguing research idea?
CD36 is commonly known as a “scavenger receptor” that binds a wide variety of ligands and is involved in many biological functions. One of the functions relates to innate immunity—the first line of defense against exogenous and endogenous molecular threats. A-beta is a ligand for CD36, but its role in the accumulation of A-beta in brain and blood vessels remained unclear. We had previously observed that removing CD36 blocked the powerful effects of A-beta on cerebral blood vessels.
Tg2576 mice, in which brain A-beta is elevated, have a profound dysfunction in neurovascular regulation, a condition that leads to a mismatch between the energy requirements of the brain and the delivery of nutrients through blood flow. However, Tg2576 mice in which CD36 was deleted using genetic approaches, had normally functioning cerebral blood vessels. Since A-beta is cleared in part through cerebral blood vessels, the normalization of cerebrovascular function by CD36 deletion raised the possibility that the accumulation of A-beta could be reduced. Therefore, the intriguing question was whether the improvement in vascular function afforded by CD36 deletion would, by itself, be sufficient to prevent the accumulation of A-beta in cerebral blood vessels (CAA) and ultimately improve cognition.
Consistent with this prediction, we found that improving vascular function led to a reduction in CAA and improvement of cognitive deficits. Remarkably, however, the improvement in A-beta accumulation was observed only in cerebral blood vessels and not amyloid plaques, highlighting the critical role of CD36 in CAA.
What's next for your research? What important questions remain regarding CD36?
The next question is to develop approaches to dampen CD36 function in order to prevent A-beta-induced cerebrovascular dysfunction and development of CAA, first in mice, and then in patients. CD36 has several ligand binding sites, one of which binds A-beta. Small molecules able to inhibit the A-beta-binding on this site need to be developed.
The challenge is to suppress CD36 signaling initiated by A-beta while preserving the other functions of CD36, such as translocation of fatty acids or innate immunity. In terms of our research, the next step is to determine the cell type(s) expressing CD36 that are involved in the interaction with A-beta in cerebral blood vessels, and the signaling pathways activated by A-beta binding to CD36 that promote CAA.
Costantino Iadecola, MD is Director of the Feil Family Brain and Mind Research Institute at Weill Cornell. He was also the Anne Parrish Titzell Professor of Neurology.