Novel characterization of vascular amyloid in CAA via CLARITY

Background Alzheimer’s Disease (AD) is a costly and expanding medical crisis that represents the major form of β‐amyloidosis affecting our aged population. Another form of cerebral β‐amyloidosis is Cerebral Amyloid Angiopathy (CAA), where β‐amyloid deposits into the cerebrovasculature instead of—or in addition to—distinct parenchymal plaques, independently contributing to cognitive decline. CAA is thought to produce weakened vascular network, eventually producing miniature cerebrovascular hemorrhagic events, microbleeds, and progressive deteriorating cognitive function. Method All previous attempts to characterize CAA microscopically have utilized thin brain sections, which are unable to discern the discrete relationship between these β‐amyloid structures and the surrounding vasculature along the entire blood vessel. We attempt to solve this limitation with the use of CLARITY, an advanced fixative technique which preserves intact cellular network structure and allows for diffusion of unfixed lipids, rendering contiguous transparent 3D tissue samples Result Through this technique, we have qualitatively determined the near‐ubiquitous nature of β‐amyloid deposition in CAA and gross vascular abnormalities of stratified intensity. Furthermore, we have determined that β‐amyloid is present at sites of microhemorrhage, a question that has remained controversial to date Conclusion This methodology will allow us to evaluate specific markers associated with vascular fragility and microhemorrhage risk and map the microvascular network to identify morphological and molecular features associated with vascular fragility. This work will provide the throughput necessary to discover tractable vascular markers for novel future therapeutics for CAA, potentially generalizable to AD.