Clearance of amyloid-β by circulating lipoprotein receptors

Abstract

Low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears amyloid β-peptide (Aβ) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Aβ in humans. Recombinant LRP cluster IV (LRP-IV) bound Aβ in plasma in mice and in Alzheimer's disease-affected humans with compromised sLRPmediated Aβ binding, and reduced Aβ-related pathology and dysfunction in a mouse model of Alzheimer mice, suggesting LRP-IV can effectively replace native sLRP and clear Aβ.LRP binds the Alzheimer's disease neurotoxin, Aβ, at the abluminal side of the blood-brain barrier (BBB), which initiates Aβ clearance from brain to blood via transcytosis across the BBB1 -4. In the liver, LRP mediates systemic clearance of Aβ5. β-secretase cleaves the Nterminus extracellular domain of LRP6, which releases soluble LRP (sLRP). sLRP normally circulates in plasma 7 .Two major binding domains of LRP, cluster II and cluster IV 8 , bind Aβ in vitro with high affinity: i.e., Aβ40 > Aβ42 (ref. 2). We hypothesized that LRP recombinant cluster IV (LRP-IV) retains its high-affinity binding for Aβ in vivo, and that this binding alters Aβ transport at the BBB, which is dominated by the cell-surface LRP1 -4 and the receptor for advanced glycation end-products (RAGE) 9 , resulting in Aβ efflux from the brain. We also hypothesized

Toll-Like Receptor 2 Acts as a Natural Innate Immune Receptor to Clear Amyloid β1–42and Delay the Cognitive Decline in a Mouse Model of Alzheimer's Disease

“…This theory actually proposes an efflux of soluble A␤ from the brain, across the blood-brain barrier, into the plasma and that this protein can be degraded in peripheral organs. Transporter and carrier proteins have been found in the blood-brain barrier to control the exchange of smaller peptides, including A␤, from the brain to the periphery (Mackic et al, 1998;Shibata et al, 2000;Sagare et al, 2007). Therefore, it is possible that peripheral immunocompetent cells, expressing TLR2 after the lentiviral injection, contribute to the A␤ clearance.…”

Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-β Protein Precursor Processing by Suppression of Cholesterol Synthesis

“…Several studies suggest that reduction of Aβ from the systemic circulation by anti-Aβ antibody [49], soluble RAGE [50], or LRP-1 [51] may be sufficient to inhibit AD development. Recently, a large cohort study showed that statins are associated with a reduced risk of developing AD.…”

Autoantibody-catalyzed Hydrolysis of Amyloid β Peptide

“…The neonatal Fc receptor expressed at the BBB may be involved in the observed effect of peripherally injected A␤ binding IgG (33). Reduced free A␤ levels in the periphery due to the A␤ binding reagents such as gelsolin and soluble lipoprotein receptors also induce increased A␤ efflux from the brain and decreased influx into the brain (34,35). The concentrations of A␤40 and A␤-(1-42) in blood are ϳ0.2 and ϳ0.05 ng/ml, respectively (4).…”