Neuronal Clearance of Amyloid-β by Endocytic Receptor LRP1

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Accumulation, aggregation, and deposition of amyloid-␤ (A␤) peptides generated through proteolytic cleavage of amyloid precursor protein (APP) are likely initiating events in the pathogenesis of AD. While A␤ production is accelerated in familial AD, increasing evidence indicates that impaired clearance of A␤ is responsible for late-onset AD. Because A␤ is mainly generated in neurons, these cells are predicted to have the highest risk of encountering A␤ among all cell types in the brain. However, it is still unclear whether they are also involved in A␤ clearance. Here we show that receptor-mediated endocytosis in neurons by the low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in brain A␤ clearance. LRP1 is known to be an endocytic receptor for multiple ligands including A␤. Conditional knock-out of Lrp1 in mouse forebrain neurons leads to increased brain A␤ levels and exacerbated amyloid plaque deposition selectively in the cortex of amyloid model APP/PS1 mice without affecting A␤ production. In vivo microdialysis studies demonstrated that A␤ clearance in brain interstitial fluid is impaired in neuronal Lrp1 knock-out mice. Because the neuronal LRP1-deletion did not affect the mRNA levels of major A␤ degrading enzymes, neprilysin and insulin-degrading enzyme, the disturbed A␤ clearance is likely due to the suppression of LRP1-mediated neuronal A␤ uptake and degradation. Together, our results demonstrate that LRP1 plays an important role in receptormediated clearance of A␤ and indicate that neurons not only produce but also clear A␤.

Cerebrospinal Fluid Peptides as Potential Parkinson Disease Biomarkers: A Staged Pipeline for Discovery and Validation*

“…The low density lipoprotein receptor-related protein 1 (LRP1) is a cell surface receptor expressed in different brain cell types including endothelial cells and neurons; it can regulate amyloid-␤ and other ligands trafficking into the cell and clearance from the brain (35,36), and maintain brain lipid homeostasis and associated synaptic and neuronal integrity (37). Increased expression of LRP1 was observed in PD brain (38) and functional soluble LRP1 was also detected in human brain tissue and CSF (39).…”

A Pro-Nerve Growth Factor (proNGF) and NGF Binding Protein, α2-Macroglobulin, Differentially Regulates p75 and TrkA Receptors and Is Relevant to Neurodegeneration Ex Vivo and In Vivo

“…LRP1 is a receptor for multiple ligands, including ␣ 2 M, myelin-associated glycoprotein (MAG), apolipoprotein E, activated complement, and amyloid ␤ (A␤). LRP1 is involved in clearance of some ligands such as ␣ 2 M, A␤, and complement through endocytosis and can regulate inflammatory mediators (43)(44)(45).…”

The Translational Significance of the Neurovascular Unit

“…A␤ cleavage products are eventually extruded through the leaky axonal membranes into the brain interstitial fluid, where they can be taken up and degraded by nearby neurons (55). Alternatively, A␤ will persist in the brain interstitial space and form amyloid plaques (54).…”