Three‐dimensional study on morphological changes of arterioles in Cerebral Amyloid Angiopathy

• Published in: Alzheimer's & dementia Vol. 18; no. S4
• Main Authors: Antunes, Lissa Ventura, Bosworth, Allison M, Nackenoff, Alex, Shostak, Alena, Snider, John C, Sturgeon, Sarah M, Merryman, David W, Solopova, Elena, Fernandez, Wilber Romero, Lippmann, Ethan S, Schrag, Matthew
• Format: Journal Article
• Language: English
• Published: 01.12.2022
• ISSN: 1552-5260; 1552-5279
• DOI: 10.1002/alz.066004

Background The accumulation of β‐amyloid plaques in the brain is a hallmark of Alzheimer’s disease. Vascular involvement is also common in the form of cerebral amyloid angiopathy (CAA), a vasculopathy that is produced when the β‐amyloid forms toxic deposits on vessels wall. The accumulation of β‐amyloid makes blood vessels stiff and increases the thickness of the vessel wall, reducing the blood flow and energy supply for the tissue. This predisposes to hemorrhage and contribute to cognitive decline and stroke. Method We used the CLARITY method to analyze tissue samples from patients with CAA to characterize changes to vessel morphology associated with vascular degeneration. The blood vessels were stained with isolectin, β‐amyloid with thiazine red, and proteins with primary antibodies associated with the vascular structure. We conducted 3D microscopy using a light sheet microscope and performed surface volume reconstruction to assess the morphology of rupturing vessel. We also measured arteriolar stiffness of vessels damaged using atomic force microscopy (AFM). Finally, we assessed cerebral blood flow and autoregulation in vivo in a novel mouse model of CAA using laser speckle flowetry. Result Vessels with CAA demonstrate an organized ring‐shaped deposits β‐amyloid. At sites, these rings are shattered and the vessel diameter increase. Degenerating vessels also demonstrate depletion of vascular smooth muscle, circumferential luminal dilation, and thickening of the vessel wall. Lysyl oxidase levels and markers of fibrosis are increased in vessels with degenerating features. We found that the arteriolar wall was more than 400% stiffer in CAA than in arterioles without CAA in the mice model. Finally, in a novel mouse model of CAA we are terming the VASC‐FAD model, resting cerebral blood flow and vasoreactivity are both reduced. Conclusion Combining the CLARITY technique associated with surface volume rendering and AFM we have a better overview of microhemorrhages to understand the vascular fragility and morphological changes, and accumulation of myofibroblast markers caused by the β‐amyloid deposition and stiffness. These features combine to alter the physiology of cerebral blood flow. Defining mechanism of microvascular degeneration in AD and CAA may lead to novel treatment targets to restore the ECM and vascular network integrity.