The relationship between amyloid-beta and brain capillary endothelial cells in Alzheimer's disease

Abstract

Neurovascular dysfunction, as an integral part of Alzheimer's disease, may have an important influence on the onset and progression of chronic neurodegenerative processes. The blood-brain barrier (BBB) pathway is one of the main pathways that mediates the clearance of amyloid-beta (Aβ) in the brain parenchyma. A large number of studies have shown that receptors and ATP-binding cassette transporters expressed on endothelial cells play an important role in Aβ transport across the BBB, but the specific mechanism is not clear. In this review, we summarize the possible mechanisms of Aβ production and clearance, and in particular the relationship between Aβ and brain capillary endothelial cells. Aβ is produced by abnormal cleavage of the amyloid precursor protein via amyloidogenic processing under pathological conditions. Dysregulation of Aβ clearance is considered to be the main reason for the massive accumulation of Aβ in the brain parenchyma. Several pathways mediating Aβ clearance from the brain into the periphery have been identified, including the BBB pathway, the blood-cerebrospinal fluid barrier and arachnoid granule pathway, and the lymphoid-related pathway. Brain capillary endothelial cells are the key components of Aβ clearance mediated by BBB. Receptors (such as LRP1, RAGE, and FcRn) and ATP-binding cassette transporters (such as P-gp, ABCA1, and ABCC1) expressed on endothelial cells play a critical role in Aβ transcytosis across the BBB. The toxic effects of Aβ can induce dysregulation of receptor and transporter expression on endothelial cells. Excessive Aβ exerts potent detrimental cerebrovascular effects by promoting oxidative stress, inducing chronic inflammation, and impairing endothelial structure and functions. All of these are main causes for the reduction in Aβ clearance across the BBB and the accumulation of Aβ in the brain parenchyma. Therefore, studies on the interactions between Aβ and brain capillary endothelial cells, including their receptors and transporters, studies on inhibition of the toxic effects of Aβ on endothelial cells, and studies on promoting the ability of endothelial cells to mediate Aβ clearance may provide new therapeutic strategies for Aβ clearance in Alzheimer's disease.

Keywords: Alzheimer’s disease; Aβclearance; amyloid beta; blood-brain barrier; cerebral amyloid angiopathy; dementia; endothelial cells; oxidative stress; review; therapeutics; transcytosis.

Figure 1

The relationship between amyloid beta (Aβ) and brain capillary endothelial cells. BBB: Brain-blood barrier.

Figure 2

Receptors and transporters mediate Aβ transport across the blood-brain barrier. ① By binding to PICALM, the Aβ-LRP1 complex is integrated into a clathrin-coated pit and then cleared from the brain via transcytosis or directed to lysosome for degradation. ② Aβ-apoE2 or Aβ-apoE3 complex binds to LRP1 and forms endophagocytic vesicles, which are then discharged at the plasma membrane on the other side of the endothelial cell via transcytosis. ③ Aβ-apoE4 complex interacts with very low density lipoprotein receptor (VLDLR) and is slowly endocytosed, then cleared from the endothelial cells by transcytosis. ④ Aβ-clusterin complex can bind to LRP2 receptor on both sides of the endothelial cell membrane for bidirectional transport, but LRP2 is usually occupied by clusterin rather than Aβ-clusterin complex on the luminal side, so the net flow is Aβ outflow. ⑤ FcRn mediates IgG-Aβ transport from the brain into blood via transcytosis. ⑥ Luminally expressed RAGE binds to circulating Aβ and transcytoses it from blood to the brain. Both FcRn- and RAGE-mediated Aβ clearance may be involved in the endosomal/lysosomal pathway. ⑦ P-gp may assist LRP1-mediated Aβ transport and pump Aβ directly into the blood from the lumenal side of endothelial cells. P-gp and BCRP also assist in the excretion of circulating Aβ transported by RAGE into endothelial cells. ⑧ ABCA1 does not directly mediate Aβ trafficking across the BBB; it promotes proteolytic degradation of Aβ in the brain parenchyma and affects the clearance of Aβ across the BBB by regulating lipogenation of apoE. ⑨ LRP1 first mediates Aβ endocytosis, and then Aβ is transported from the abluminal side to the luminal side of the endothelial cells. Subsequently, P-gp and ABCC1 export Aβ from the luminal membrane of endothelial cells to the systemic circulation. ApoE: apolipoprotein E; Aβ: amyloid-beta; BCRP(ABCG2): breast cancer resistance protein; LRP: low density lipoprotein receptor(LDLR)-related protein; P-gp: P-glycoprotein; PICALM: phosphatidylinositol binding clathrin assembly protein; RAGE: advanced glycation end products; VLDLR: very low density lipoprotein receptor.

Figure 3

Receptors and transporters on endothelial cells may be potential targets for therapies designed to promote Aβ clearance. Upregulation of MEOX2 expression and downregulation of SRF/MYOCD expression can restore LRP1 levels and increase Aβ removal from the brain parenchyma. Upregulation of PICALM expression can increase Aβ-LRP1 complex endothelial transcytosis. Activation of PXR can upregulate the expression of P-gp, thereby promoting Aβ efflux from the brain. Activation of LXR can mediate upregulation of ABCA1, decreasing Aβ levels in the brain. Some tertiary amides block the interaction between RAGE and Aβ, precluding Aβ from reentering the brain. Downregulation of endothelial CCR5 expression can prevent the Aβ-RAGE complex from transmitting signals to the immune system. The blue line in the figure represents mediated Aβ outflow; the brown line represents mediated Aβ inflow; the green line represents activation or inhibition; solid lines represent receptors or transporters that directly mediate Aβ transport; dashed lines represent receptors or transporters that indirectly mediate Aβ transport. Aβ: Amyloid-beta; LRP1: low density lipoprotein receptor(LDLR)-related protein 1; LXR: Liver X Receptor; MEOX2: mesenchyme homeobox gene 2; MYOCD: myocardin; P-gp: P-glycoprotein; PICALM: phosphatidylinositol binding clathrin assembly protein; PXR: pregnane X receptor; RAGE: advanced glycation end products; SRF: serum response factor.