Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to Aβ deposition and lysyl oxidase.

INTRODUCTION

The morphological and molecular changes associated with the degeneration of arterioles in cerebral amyloid angiopathy (CAA) are incompletely understood.

METHODS

Post mortem brains from 26 patients with CAA or neurological controls were analyzed using light-sheet microscopy, and morphological features of microvascular degeneration were quantified using surface volume rendering. Vascular stiffness was analyzed using atomic force microscopy.

RESULT

Vascular smooth muscle cells (VSMCs) volume was reduced by ≈ 55% in CAA. This loss of VSMC volume correlated with increased arteriolar diameter, variability in diameter, and the volume of amyloid beta (Aβ) deposition in the vessel. Vessels with CAA were > 300% stiffer than controls. The volume of extracellular matrix cross-linking enzyme lysyl oxidase (LOX) correlated closely with vascular degenerative features.

DISCUSSION

Our findings provide valuable insights into the connections among LOX, Aβ deposition, and vascular stiffness in CAA. Restoration of physiologic extracellular matrix properties in penetrating arteries may yield a novel therapeutic strategy for CAA.

HIGHLIGHTS

We conducted 3D microscopy on human brains with cerebral amyloid angiopathy. We quantified features of vascular degeneration, β-amyloid, and lysyl oxidase in CAA Vascular degeneration correlated with Aβ, loss of VSMCs , and increased LOX. Arterioles with CAA were stiffer than controls in data from atomic force microscopy. Vascular extracellular matrix properties may be a therapeutic target for CAA.