Clearance of amyloid-beta by circulating lipoprotein receptors - PubMed (original) (raw)

. 2007 Sep;13(9):1029-31.

doi: 10.1038/nm1635. Epub 2007 Aug 12.

Rashid Deane, Robert D Bell, Bradley Johnson, Katie Hamm, Ronan Pendu, Andrew Marky, Peter J Lenting, Zhenhua Wu, Troy Zarcone, Alison Goate, Kevin Mayo, David Perlmutter, Mireia Coma, Zhihui Zhong, Berislav V Zlokovic

Affiliations

Clearance of amyloid-beta by circulating lipoprotein receptors

Abhay Sagare et al. Nat Med. 2007 Sep.

Abstract

Low-density lipoprotein receptor-related protein-1 (LRP) on brain capillaries clears amyloid beta-peptide (Abeta) from brain. Here, we show that soluble circulating LRP (sLRP) provides key endogenous peripheral 'sink' activity for Abeta in humans. Recombinant LRP cluster IV (LRP-IV) bound Abeta in plasma in mice and Alzheimer's disease-affected humans with compromised sLRP-mediated Abeta binding, and reduced Abeta-related pathology and dysfunction in a mouse model of Alzheimer disease, suggesting that LRP-IV can effectively replace native sLRP and clear Abeta.

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Figures

Figure 1

Figure 1

LRP-IV clears mouse endogenous brain Aβ improves function and clears human brain Aβ in APP+/sw mice. (a,b) Brain levels (a) and total plasma levels (b) of mouse endogenous Aβ40 and Aβ42 in vehicle-treated (white) and LRP-IV-treated (intravenously for 5 d, 20 µg/day) mice (black) Values are means ± s.e.m., n = 3–5 mice per group. (c) Percent increase in cerebral blood flow (CBF) in response to whisker stimulation in littermate controls (gray) and APP+/sw mice treated with vehicle (white) or LRP-IV (black). (d–f) Operant learning at day 1 and 2 (d), novel object location (e) and novel object recognition (f) expressed as percentage exploratory preference in littermate controls (gray) and APP+/sw mice treated with vehicle (white) or LRP-IV (black). (g,h) Aβ40 and Aβ42 levels in hippocampus (g) and cortex (h) of APP+/sw mice treated with vehicle or LRP-IV. In c–h, LRP-IV (40 µg per kg body weight per day) was administered intraperitioneally for 3 months beginning at age 6 months. Values are means ± s.e.m., n = 8 mice per group. All procedures with wild-type mice and APP+/sw mice were according to US NIH guidelines approved by the University Committee on Animal Resources, University of Rochester.

Figure 2

Figure 2

LRP-IV controls Aβ pathology in APP+/sw mice and sLRP and LRP-IV regulate peripheral Aβ in Alzheimer’s disease. (a) Aβ immunostaining in APP+/sw mice treated with vehicle or LRP-IV. (b) X-34 staining for amyloid (blue) and CD31 immunostaning for vascular endothelium (red) in APP+/sw mice treated with vehicle or LRP-IV. Insets: left, amyloid in the pial vessel on the surface of the brain in vehicle-treated mice; right, absence of amyloid in the pial vessel in LRP-IV treated mice. (c) Total plasma Aβ40 and Aβ42 levels in vehicle-treated (white bars) and LRP-IV-treated (black bars) mice. In a–c, LRP-IV (40 µg per kg body weight per day) was administered intraperitoneally for 3 months beginning at the age of 6 months. Values are means ± s.e.m., n = 8 mice per group. (d) Plasma sLRP levels in individuals without (non-AD; white) and with (AD; black) Alzheimer’s disease. Means ± s.e.m., from 36 non-AD and 44 AD individuals. (e) Oxidized sLRP (carbonyl content) in plasma of non-AD (white) and AD (black) individuals. Means ± s.e.m. from 12 non-AD and 16 AD individuals. (f,g) sLRP-bound Aβ40 and Aβ42, free Aβ40 and Aβ42 (<30 kDa), and Aβ40 and Aβ42 associated with other plasma proteins (>30 kDa) in non-AD controls (white) and AD individuals (black). Means ± s.e.m., n = 18 per group. (h) Effect of LRP-IV on redistribution of different Aβ40 and Aβ42 pools in AD plasma. Means ± s.e.m., n = 6. All procedures with AD mice were according to the NIH guidelines approved by the University Committee on Animal Resources, University of Rochester. The experiments involving human subjects have been approved by the Institutional Review Board Committee of the Washington University School of Medicine through the Alzheimer’s Disease Research Center. Informed consent was obtained from all subjects.

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