LRP-Mediated Clearance of Aβ is Inhibited by KPI-Containing Isoforms of APP

The pathogenesis of Alzheimer's disease (AD) involves the abnormal accumulation and deposition of β- amyloid in cerebral blood vessels and in the brain parenchyma. Critical in modulating β-amyloid deposition in brain is the flux of Aβ across the blood brain barrier. The low-density lipoprotein receptor-related protein (LRP), is a large endocytic receptor that mediates the efflux of Aβ out of brain and into the periphery. The first step in the LRP-mediated clearance of Ab involves the formation of a complex between Aβ and the LRP ligands apolipoprotein E (apoE) or α2-macroglobulin (α2M). The Aβ / chaperone complexes then bind to LRP via binding sites on apoE or α2M. The efflux of Aβ / chaperone complexes out of the neuropil and into the periphery may be attenuated by LRP-ligands that compete with apoE or α2M for LRP binding. LRP is also the cell surface receptor for Kunitz Protease Inhibitor (KPI) containing isoforms of Ab's parent protein, the amyloid protein precursor (APP). Protein and mRNA levels of KPI-containing APP isoforms (APP-KPI) are elevated in AD brain and are associated with increased Ab production. In this study we show that soluble non-amyloidogenic APP-KPI can also inhibit the uptake of Aβ / α2M in a cell culture model of LRP mediated Aβ clearance. Clearance of Aβ / apoE complexes was not inhibited by APP-KPI. Our findings are consistent with studies showing that apoE and α2M have discrete binding sites on LRP. Most significantly, our data suggests that the elevated levels of APP-KPI in AD brain may attenuated the clearance of Aβ, the proteins own amyloidogenic catabolic product.