LRP1 in Brain Vascular Smooth Muscle Cells Mediates Local Clearance of Alzheimer's Amyloid-β

Impaired clearance of amyloid-beta (A beta) is a major pathogenic event for Alzheimer's disease (AD). A beta depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain A beta clearance is the cerebrovascular system where A beta is eliminated through the blood-brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An A beta clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in cerebrovasculature, in particular in vascular smooth muscle cells. Previous studies have indicated a role of LRP1 in endothelial cells in transcytosing A beta out of the brain across the BBB; however, whether this represents a significant pathway for brain A beta clearance remains controversial. Here, we demonstrate that A beta can be cleared locally in the cerebrovasculature by an LRP1-dependent endocytic pathway in smooth muscle cells. The uptake and degradation of both endogenous and exogenous A beta were significantly reduced in LRP1-suppressed human brain vascular smooth muscle cells. Conditional deletion of Lrp1 in vascular smooth muscle cell in amyloid model APP/PS1 mice accelerated brain A beta accumulation and exacerbated A beta deposition as amyloid plaques and CAA without affecting A beta production. Our results demonstrate that LRP1 is a major A beta clearance receptor in cerebral vascular smooth muscle cell and a disturbance of this pathway contributes to A beta accumulation. These studies establish critical functions of the cerebrovasculature system in A beta metabolism and identify a new pathway involved in the pathogenesis of both AD and CAA.