Transport Pathways for Clearance of Human Alzheimer's Amyloid β-Peptide and Apolipoproteins E and J in the Mouse Central Nervous System

By R. Bell, A. Sagare, A. Friedman, G. Bedi, D. Holtzman, R. Deane, Berislav Zlokovic. Journal of Cerebral Blood Flow and Metabolism, 2007

687 citations recorded by the source corpus.

Amyloid β-peptide (Aβ) clearance from the central nervous system (CNS) maintains its low levels in brain. In Alzheimer's disease, Aβ accumulates in brain possibly because of its faulty CNS clearance and a deficient efflux across the blood—brain barrier (BBB). By using human-specific enzyme-linked immunosorbent assays, we measured a rapid 30 mins efflux at the BBB and transport via the interstitial fluid (ISF) bulk flow of human-unlabeled Aβ and of Aβ transport proteins, apolipoprotein E (apoE) and apoJ in mice. We show (i) Aβ40 is cleared rapidly across the BBB via low-density lipoprotein receptor-related protein (LRP)1 at a rate of 0.21 pmol/min g ISF or 6-fold faster than via the ISF flow; (ii) Aβ42 is removed across the BBB at a rate 1.9-fold slower compared with Aβ40; (iii) apoE, lipid-poor isoform 3, is cleared slowly via the ISF flow and across the BBB (0.03–0.04 pmol/min g ISF), and after lipidation its transport at the BBB becomes barely detectable within 30 mins; (iv) apoJ is eliminated rapidly across the BBB (0.16 pmol/ming ISF) via LRP2. Clearance rates of unlabeled and corresponding 125I-labeled Aβ and apolipoproteins were almost identical, but could not be measured at low physiologic levels by mass spectrometry. Amyloid β-peptide 40 binding to apoE3 reduced its efflux rate at the BBB by 5.7-fold, whereas Aβ42 binding to apoJ enhanced Aβ42 BBB clearance rate by 83%. Thus, Aβ, apoE, and apoJ are cleared from brain by different transport pathways, and apoE and apoJ may critically modify Aβ clearance at the BBB.

Subfields: Biochemistry, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/365791a67c85d9a96b692268f7310e50c51e2c7c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biochemistry

1. Berislav Zlokovic
2. P. Tontonoz

In Oncology

1. Berislav Zlokovic
2. D. Holtzman
3. G. Bu
4. P. Tontonoz
5. N. Zelcer
6. R. Bell

In Physiology

1. D. Holtzman
2. Berislav Zlokovic
3. G. Bu
4. J. Herz
5. A. Goate
6. A. Sagare
7. R. Bell
8. John C. Morris

Citations in the corpus

• The role of microglia in amyloid clearance from the AD brain (2010, background): “The efflux of Ab through these mechanisms has been postulated to be facilitated or inhibited by its binding to chaperone proteins, such as ApoE, ApoJ, a2-macroglobulin, transthyretin and albumin (Bell et al. 2007; Deane and Zlokovic 2007; Narita et al. 1997; Zlokovic et al. 1996).”
• Human apoE isoforms differentially regulate brain amyloid-β peptide clearance (2011, positive): “Indeed, several studies have demonstrated that Aβ transport from brain into blood is altered when complexed to human apoE (55, 56).”
• apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. (2008, methodology): “According to our model (see Methods), the elimination of inulin from brain ISF (Figure 1A) reflects a passive drainage of molecules via the ISF bulk flow, as reported (16, 17, 19).”
• The blood-brain barrier in health and chronic neurodegenerative disorders. (2008, positive): “Binding of Ab to LRP1 at the abluminal side of the BBB initiates Ab clearance from brain to blood via transcytosis across the BBB (Figure 5A) (Shibata et al., 2000; Deane et al., 2004a; Cirrito et al., 2005; Bell et al., 2007).”
• Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer’s disease (2009, background): “Understanding the specific Ab– LRP interactions will greatly advance our understanding of iv Aβ i ii iii iv (1) LRP transcytosis (2) sLRP "sink" in plasma ii iii iv (6) Perivascular space (3) ApoE in ISF (4) Microglia/perivascular macrophages (5) Enzymatic degradation i ii iii iv ii iii iv LRP sLRP ”
• Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. (2012, background): “E2) (Bell et al. 2007; Ito et al. 2007; Deane et al. 2008).”
• ApoE promotes the proteolytic degradation of Abeta. (2008, background): “ApoE lipidation status is also a significant determinant of whether its interaction with Aβ leads to efflux of the peptides from the brain, or alternatively to the formation of fibrils and their deposition into plaques (Bell et al., 2007; LaDu et al., 1995; Morikawa et al., 2005; Tokuda et al., 2000”
• The Role of Apolipoprotein E in Alzheimer’s Disease (2009, background): “ApoE has been shown to slow the transport of Aβ across the BBB in an isoform-dependent manner (E4>E3>E2) (Bell et al., 2007; Deane et al., 2008; Ito et al., 2007).”