15 Aug 2007

Passive immunotherapy for Alzheimer disease relies on circulating anti-amyloid antibodies to lure amyloid-β (Aβ) peptides out of brain tissues. Now, Berislav Zlokovic and colleagues at the University of Rochester Medical School in New York unveil an entirely new way to clear amyloid, by taking advantage of a natural Aβ-binding protein found in blood. In research published in this week’s edition of Nature Medicine online, the investigators identify a soluble fragment of the low-density lipoprotein receptor-related protein-1 (LRP) as a major peripheral sink for Aβ in humans. Using a mouse model of AD, they demonstrate that boosting the capacity of the sink by administering a recombinant form of soluble LRP reduces brain amyloid and improves learning and memory. Coupled with their observation that people with Alzheimer disease have depressed serum sLRP, the results suggest that exogenously administered, recombinant sLRP could provide a novel approach to reduce or reverse the age-related buildup of Aβ in brain.

Zlokovic and colleagues previously discovered that LRP, a membrane receptor for the AD-related proteins apolipoprotein E and α2-macroglobulin, mediates clearance of Aβ across the blood-brain barrier (Shibata et al., 2000). LRP has been implicated in AD in other ways as well. An LRP gene polymorphism is associated with AD risk, and the protein is involved in the trafficking and processing of the amyloid precursor protein (APP) to produce Aβ (see review by Waldron et al., 2006). Recently, LRP was discovered to be a substrate for the APP-cleaving enzyme β-secretase, which releases a soluble Aβ-binding fragment that circulates in the blood (von Arnim et al., 2005).

Could this little piece of LRP be acting as an Aβ sink? To address that question, first authors Abhay Sagare, Rashid Deane, and Robert Bell produced a recombinant fragment of the protein (LRP-IV) that contained the cluster IV Aβ binding domains and retained high affinity binding to Aβ in vitro. A 5-day infusion of the protein in mice caused a 51 percent decrease in endogenous brain Aβ40 and a 27 percent decrease in Aβ42, accompanied by an increase in plasma levels of both peptides, mostly associated with LRP-IV.

To test the actions of LRP-IV in an AD model, the researchers gave human APP-expressing AD mice daily intraperitoneal protein injections for 3 months, starting at 6 months of age. After the regimen, they found Aβ levels were reduced 60-70 percent in the hippocampus, and up to 90 percent in the cortex. The treatment removed both vascular and parenchymal amyloid, and increased plasma Aβ, about half of which was associated with LRP-IV. The mice showed functional improvements as well, with a return of learning and memory to normal levels. LRP-IV had no behavioral effect on wild-type mice. Treating 11-month-old mice resulted in similar clearance of brain and vascular amyloid, but no behavioral results were reported for the older mice.

Moving from mice to people, the investigators discovered that the sLRP sink appears to be impaired in people with AD. A group of AD patients showed an average of 30 percent lower sLRP levels compared to non-demented people. In samples of human plasma from normal elderly subjects, 70 percent of total Aβ40 and 90 percent of Aβ42 were bound to sLRP. People with AD showed a drop in sLRP-bound Aβ and a three- to fourfold increase in free Aβ. Adding LRP-IV to plasma from AD patients increased bound Aβ and reduced free.

“We have demonstrated that native sLRP normally controls 70-90 percent of circulating Aβ in humans through peripheral binding,” the authors write. “This sLRP function is compromised in Alzheimer’s disease, which may contribute to elevated brain Aβ.” Because recombinant LRP-IV doesn’t penetrate the brain (or CSF, they also showed), but appears to lower Aβ through peripheral binding alone, the protein could serve as an Aβ clearance and sLRP replacement therapy for Alzheimer disease, they conclude.—Pat McCaffrey

Comments

1. • Cynthia Lemere
     Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School
   • Posted: 27 Aug 2007
   • Paper: Clearance of amyloid-beta by circulating lipoprotein receptors.

   Sagare et al. report for the first time, the ability of systemically administered Aß-binding, recombinant soluble LRP cluster IV (sLRP-IV) to lower cerebral Aß levels and increase peripheral Aß in plasma. This provides proof-of-concept that sLRP-IV may have therapeutic potential for the prevention and, possibly, the treatment of AD.

   The authors suggest that sLRP-IV has potential as a systemic Aß-lowering therapy by virtue of its ability to enhance cerebral blow flow, enhance efflux of Aß from brain to blood, and prevent re-uptake of Aß from blood to brain. As a result, and based on their APP tg mouse studies, they predict that such a treatment will prevent or reduce Aß deposition in brain, thereby staving off plaque-associated changes such as gliosis and neuritic dystrophy and preventing learning and memory deficits.

   View all comments by Cynthia Lemere

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References

Paper Citations

1. Shibata M, Yamada S, Kumar SR, Calero M, Bading J, Frangione B, Holtzman DM, Miller CA, Strickland DK, Ghiso J, Zlokovic BV. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 2000 Dec;106(12):1489-99. PubMed.
2. Waldron E, Jaeger S, Pietrzik CU. Functional role of the low-density lipoprotein receptor-related protein in Alzheimer's disease. Neurodegener Dis. 2006;3(4-5):233-8. PubMed.
3. von Arnim CA, Kinoshita A, Peltan ID, Tangredi MM, Herl L, Lee BM, Spoelgen R, Hshieh TT, Ranganathan S, Battey FD, Liu CX, Bacskai BJ, Sever S, Irizarry MC, Strickland DK, Hyman BT. The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate. J Biol Chem. 2005 May 6;280(18):17777-85. PubMed.

Further Reading

News

1. Keystone Symposia Meeting, Part 7—Aβ Clearance 21 Apr 2006