It’s not that Alzheimer’s disease patients make too much brain Aβ; they’re slow at purging it—but why? Research published online September 1 in the Journal of Clinical Investigation suggests that ATP binding cassette (ABC) transporters may be involved. Jens Pahnke of the German Center for Neurodegenerative Diseases (DZNE) in Rostock, and colleagues generated AD mouse models lacking specific ABC transport proteins, and found that more brain amyloid piles up in animals with no ABCC1. What’s more, treating these mice with an ABCC1-activating cancer drug reduced Aβ load in both asymptomatic and diseased animals. The data beef up the case for ABC transporters as key regulators of Aβ clearance, and suggest these enzymes warrant a closer look as AD pharmacologic targets.

ABC transporters harness the energy of ATP to escort drugs, metabolites, and other substrates across the plasma membrane. Among the seven subfamilies (ABCA to ABCG), three contain proteins that have been shown to pump Aβ across the blood-brain barrier. An in-vitro study (Lam et al., 2001) identifying P-glycoprotein (aka ABCB1) as one such Aβ transporter prompted Pahnke and colleagues to look at ABCB1 levels in patient brains. The researchers found, indeed, that seniors with less ABCB1 in their brain epithelium had more plaque (Vogelgesang et al., 2002) and more vascular Aβ (Vogelgesang et al., 2004). A similar trend showed up in AD transgenic mice (see ARF related news story on Cirrito et al., 2005). ABCA1 (Koldamova et al., 2005) and ABCG2 (Xiong et al., 2009) can also export Aβ. ABCA7 came up as a hit in a recent AD genomewide association study (ARF related news story on Hollingworth et al., 2011), and currently sits in the fourth position in the AlzGene Top Results.

In the current paper, researchers led by joint first authors Markus Krohn and Cathleen Lange generated APP/PS1 mice deficient in ABCB1, ABCG2, or ABCC1 to study how these transport proteins regulate Aβ clearance. Because the researchers had wanted to focus on ABCB1, the latter two strains were meant as controls, “but early on we noticed that the mice with no C1 transporter had more brain amyloid than the other two lines,” Pahnke told ARF. Comparing the three strains by Aβ immunochemistry, ABCC1-deficient AD mice had the largest plaques and, by ELISA, 12- to 14-fold more brain Aβ than control AD mice. Brain amyloid levels were up two- to fourfold in ABCB1-deficient mice, while ABCG2-deficient animals looked comparable to controls. The dramatic changes seen in ABCC1-/- AD mice did not stem from abnormal processing of amyloid precursor protein (APP) or microglial activation. Moreover, the researchers saw similar effects when they crossed ABCC1-knockout mice with a less aggressive strain (APP Dutch) that develops amyloidosis around 24 months of age, as opposed to six to eight weeks for APP/PS1 mice.

Measuring Aβ42 transport across mouse capillary endothelial cells in vitro, the scientists determined that APP/PS1 mice lacking ABCC1 were 60 percent less efficient at exporting Aβ compared to their ABCC1+/+ counterparts. Considering this defect alongside other factors that affect rates of synthesis and removal of Aβ, Pahnke’s team came up with a mathematical model that predicted an 11 percent overall reduction in Aβ clearance in ABCC1-/- AD mice. Last year, scientists measured real-time Aβ turnover in the cerebrospinal fluid of AD patients and found they get rid of brain Aβ about 30 percent more slowly than age-matched controls (ARF related news story on Mawuenyega et al., 2010).

ABCC1 is also expressed at the choroids plexus, suggesting that in addition to playing a role at the blood-brain barrier, it may actively clear Aβ from the CSF as well, noted John Cirrito, Washington University School of Medicine, St. Louis, Missouri, in an e-mail to ARF (see comment below). Kwasi Mawuenyega, a Washington University scientist who was first author of the 2010 study on real-time Aβ dynamics in people, called the new data “exciting” and said the paper provides “a valuable clue for proving causality of impaired Aβ clearance for AD (see comment below).”

Next, Pahnke and colleagues explored whether boosting the enzyme’s function would relieve the amyloid burden in the brains of APP/PS1 mice. They treated the animals with an FDA-approved anti-nausea drug (thiethylperazine) that drives up ABCC1 transport activity in vitro by 69 percent. They tested preventive and therapeutic strategies. The former involved 30 days of twice-daily intramuscular drug injections begun at 45 days of age, before this strain develops plaques; for the latter, a 25-day oral treatment started when disease is underway at 75 days of age. “Both paradigms were able to reduce plaques and soluble Aβ in the brain,” Pahnke said. He and colleagues did not test whether the drug crosses the blood-brain barrier, or how it is metabolized, in mice. “For the effect we want, it doesn’t need to get into the brain,” he told ARF. “We think this drug circulates in the blood, activates the transporter, and by doing so reduces the amount of soluble Aβ in the brain. By reducing the soluble forms (i.e., dimers, monomers), it prevents the growth of plaques.”

Pahnke and colleagues are now recruiting elderly couples for a genetic study to identify ABCC1 polymorphisms, and for a Phase 1 trial of thiethylperazine set to begin next year. In addition, the researchers are trying to develop a brain imaging assay for ABCC1 function to see if declining activity might portend neurodegenerative disease. Toward that end, they are planning a positron emission tomography (PET) study that will use a radiolabeled ABCC1 inhibitor to track transport activity in the brain. PET studies have found decreased ABCB1 function in disease-specific brain regions of people with Parkinson’s disease, progressive supranuclear palsy, and corticobasal degeneration (Kortekaas et al., 2005; Bartels et al., 2008; Bartels et al., 2000; see also review by Bartels, 2011). “The hypothesis is that decreased transport in specific brain areas leads to accumulation of proteins, thus to neurodegenerative disease, not only AD,” Pahnke said.—Esther Landhuis

Comments

Make a Comment

To make a comment you must login or register.

Comments on News and Primary Papers

  1. Dr. Krohn and colleagues have identified another Aβ transporter at the CNS-blood barrier, ABCC1. Interestingly, this particular transporter is highly expressed at the choroid plexus, suggesting that, in addition to playing a role at the blood-brain barrier (BBB), it may actively clear Aβ from the CSF as well. Several groups have published BBB Aβ transporters, while CSF-blood transporters have been much less studied. It will be interesting to see how ABCC1 changes in the setting of AD as well as prior to AD (in individuals at risk for AD).

    Given some of Dr. Randy Bateman’s recent findings that Aβ clearance is impaired in AD patients, identifying transporters such as this may provide key insights to disease pathogenesis. Dr. Bateman’s studies assessed CSF Aβ clearance in humans; it would be interesting to know the extent to which ABCC1 contributed in those studies. While anti-Aβ therapies may be able to target both production and clearance mechanisms; enhancing ABCC1 transport activity may be a useful target to augment the latter.

    View all comments by John Cirrito
  2. This is a great finding. We have all along suspected that there may be a transport mechanism for Aβ through the blood-brain barrier. In our previous article, we thought that impaired clearance of Aβ may be responsible for late-onset AD through impaired transport across the blood-brain barrier or impaired cerebrospinal fluid (CSF) transport (Mawuenyega et al. 2010). However, the evidence was not there to support our speculation. This paper provides what may be one of the missing links in the transport of Aβ through the blood-brain barrier. If this transport is impaired for late-onset AD, that will explain why CSF has low Aβ amounts with respect to high cerebral Aβ accumulation. Mechanisms of increased Aβ production may include alterations in γ- or β-secretase activity; however, there is evidence now showing that impaired clearance definitely leads to cerebral accumulation of Aβ. This article has provided a valuable clue as to prove causality of impaired Aβ clearance for AD, and that is exciting.

    View all comments by Kwasi Mawuenyega

References

News Citations

  1. Escort Service: P-Glycoprotein Ushers Aβ from Brain
  2. Large Genetic Analysis Pays Off With New AD Risk Genes
  3. Paper Alert: In Vivo Human Data Shows Reduced Aβ Clearance in AD

Paper Citations

  1. . beta-Amyloid efflux mediated by p-glycoprotein. J Neurochem. 2001 Feb;76(4):1121-8. PubMed.
  2. . Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics. 2002 Oct;12(7):535-41. PubMed.
  3. . The role of P-glycoprotein in cerebral amyloid angiopathy; implications for the early pathogenesis of Alzheimer's disease. Curr Alzheimer Res. 2004 May;1(2):121-5. PubMed.
  4. . P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest. 2005 Nov;115(11):3285-90. PubMed.
  5. . Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem. 2005 Dec 30;280(52):43224-35. PubMed.
  6. . ABCG2 is upregulated in Alzheimer's brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Abeta(1-40) peptides. J Neurosci. 2009 Apr 29;29(17):5463-75. PubMed.
  7. . Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011 May;43(5):429-35. PubMed.
  8. . Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010 Dec 24;330(6012):1774. PubMed.
  9. . Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol. 2005 Feb;57(2):176-9. PubMed.
  10. . Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA. J Neural Transm. 2008 Jul;115(7):1001-9. PubMed.
  11. . Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: a possible role in progressive neurodegeneration. Neurobiol Aging. 2009 Nov;30(11):1818-24. PubMed.
  12. . Blood-brain barrier P-glycoprotein function in neurodegenerative disease. Curr Pharm Des. 2011;17(26):2771-7. PubMed.

Other Citations

  1. APP/PS1 mice

External Citations

  1. ABCA7
  2. AlzGene Top Results

Further Reading

Papers

  1. . Blood-brain barrier P-glycoprotein function in neurodegenerative disease. Curr Pharm Des. 2011;17(26):2771-7. PubMed.
  2. . The role of P-glycoprotein in cerebral amyloid angiopathy; implications for the early pathogenesis of Alzheimer's disease. Curr Alzheimer Res. 2004 May;1(2):121-5. PubMed.
  3. . beta-Amyloid efflux mediated by p-glycoprotein. J Neurochem. 2001 Feb;76(4):1121-8. PubMed.
  4. . Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics. 2002 Oct;12(7):535-41. PubMed.
  5. . Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010 Dec 24;330(6012):1774. PubMed.

Primary Papers

  1. . Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. J Clin Invest. 2011 Oct;121(10):3924-31. PubMed.