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. 2017 Nov 6;214(11):3151-3169.
doi: 10.1084/jem.20171406. Epub 2017 Oct 23.

Alzheimer's Disease: A Matter of Blood-Brain Barrier Dysfunction?

Free PMC article

Alzheimer's Disease: A Matter of Blood-Brain Barrier Dysfunction?

Axel Montagne et al. J Exp Med. .
Free PMC article


The blood-brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer's disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.


Figure 1.
Figure 1.
Contribution of BBB breakdown and dysregulated BBB transport to AD pathophysiology based on findings in animal models, as shown in Tables 1 and 2. BBB breakdown (left) leads to perivascular accumulation of blood-derived neurotoxic products in the brain, such as red blood cell (RBC)–derived hemoglobin (Hb) and free iron (Fe2+) generating reactive oxygen species (ROS) and oxidant stress to neurons; potentially toxic plasma proteins such as fibrin(ogen), plasmin(ogen), thrombin, and/or autoantibodies, which could lead to neuronal injury, cell death, and inflammatory response; and albumin contributing to the development of edema, hypoperfusion, and tissue hypoxia. Pericyte detachment, degeneration, and loss leads to BBB breakdown. Apolipoprotein E (APOE) isoforms differentially regulate pericyte metabolism and BBB integrity. APOE2 and APOE3, but not APOE4, act via low-density lipoprotein receptor–related protein-1 (LRP1) on pericytes to inhibit the proinflammatory cyclophilin A (CypA)–matrix metallopeptidase-9 (MMP-9) pathway. When activated by APOE4, this pathway leads to MMP-9–mediated degradation of BBB tight junction and basement membrane proteins causing BBB breakdown. Dysregulated BBB transport (right) leads to a loss of equilibrium between Alzheimer’s amyloid β (Aβ) efflux and influx across the BBB, which is a key mechanism that maintains brain Aβ homeostasis. Aβ efflux is normally mediated via its receptors on brain endothelium, including LRP1, which works closely with phosphatidylinositol-binding clathrin assembly protein (PICALM) to clear Aβ monomers, oligomers, and aggregates from brain across the BBB; LRP2, which clears Aβ in a form of complexes with APOJ (clusterin); and P-glycoprotein (Pgp), which mediates active efflux of Aβ from brain endothelium to blood. LRP1 and Pgp BBB levels are reduced in AD models before Aβ deposition, which contributes to Aβ accumulation in the brain. Aβ influx from blood to brain is mediated by the receptor for advanced glycation end products (RAGE), which also triggers an inflammatory response. RAGE expression at the BBB is increased in AD models, which contributes to Aβ accumulation in the brain and inflammatory response. APOE isoforms differentially regulate Aβ clearance. Aβ complexes with human APOE2 and APOE3 isoforms are cleared across the BBB by LRP1. APOE4 has lower affinity for LRP1 and binds to the very-low-density lipoprotein receptor (VLDLR), which slowly transports its ligands across the BBB, including the APOE4–Aβ complex, causing its accumulation in the brain. BBB GLUT1 transporter delivers glucose to the brain across the BBB and is down-regulated in AD models. Its reduction accelerates BBB breakdown and Aβ pathology and leads to tau pathology and neuronal loss. BBB MFSD2a (major facilitator superfamily domain–containing protein 2) transports essential ω-3 fatty acids into the brain, which is essential for brain development, cognition, and maintenance of BBB integrity. Aβ can also accumulate in the perivascular space (PVS) between astrocyte end-feet and the vessel wall because of inefficient drainage along the perivascular route.

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