| First Author | Van Gool B | Year | 2019 |
| Journal | Mol Neurobiol | Volume | 56 |
| Issue | 10 | Pages | 7234-7245 |
| PubMed ID | 31004319 | Mgi Jnum | J:289228 |
| Mgi Id | MGI:6434693 | Doi | 10.1007/s12035-019-1594-2 |
| Citation | Van Gool B, et al. (2019) LRP1 Has a Predominant Role in Production over Clearance of Abeta in a Mouse Model of Alzheimer's Disease. Mol Neurobiol 56(10):7234-7245 |
| abstractText | The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-beta (Abeta) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Abeta from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Abeta in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Abeta metabolism showed that, despite reduced Abeta clearance due to LRP1 inactivation in vivo, less Abeta was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Abeta-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Abeta and an increase of soluble APP-alpha (sAPP-alpha). This shift in APP processing resulted in overall lower Abeta levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Abeta generation overrules the simultaneous impaired Abeta clearance, resulting in less extracellular Abeta and reduced plaque deposition in a mouse model of AD. |
