| First Author | Kanekiyo T | Year | 2012 |
| Journal | J Neurosci | Volume | 32 |
| Issue | 46 | Pages | 16458-65 |
| PubMed ID | 23152628 | Mgi Jnum | J:192453 |
| Mgi Id | MGI:5465209 | Doi | 10.1523/JNEUROSCI.3987-12.2012 |
| Citation | Kanekiyo T, et al. (2012) LRP1 in brain vascular smooth muscle cells mediates local clearance of Alzheimer's amyloid-beta. J Neurosci 32(46):16458-65 |
| abstractText | Impaired clearance of amyloid-beta (Abeta) is a major pathogenic event for Alzheimer's disease (AD). Abeta 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 Abeta clearance is the cerebrovascular system where Abeta is eliminated through the blood-brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Abeta 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 Abeta out of the brain across the BBB; however, whether this represents a significant pathway for brain Abeta clearance remains controversial. Here, we demonstrate that Abeta 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 Abeta 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 Abeta accumulation and exacerbated Abeta deposition as amyloid plaques and CAA without affecting Abeta production. Our results demonstrate that LRP1 is a major Abeta clearance receptor in cerebral vascular smooth muscle cell and a disturbance of this pathway contributes to Abeta accumulation. These studies establish critical functions of the cerebrovasculature system in Abeta metabolism and identify a new pathway involved in the pathogenesis of both AD and CAA. |
