The ABC(A1)'s of Human ApoE—More Evidence for Isoform Differences

Researchers have found yet more evidence that the ApoE4 genotype renders its carriers sensitive to lipid-related alterations and Alzheimer’s pathology. Scientists led by Radosveta Koldamova at the University of Pittsburgh, Pennsylvania, reported that a depletion of the ATP-binding cassette transporter A1 (ABCA1)—which shuttles lipids to ApoE—fans the flames of cognitive problems and Aβ deposition in transgenic mice carrying the human ApoE4 gene, but not in animals with the ApoE3 isoform. Published September 19 in the Journal of Neuroscience, the study could have implications for ApoE-related treatments.

"This paper highlights the selective vulnerability of the ApoE4 genotype to disease-related changes in Aβ homeostasis," said Gary Landreth, Case Western Reserve University, Cleveland, Ohio. Landreth was not involved in the study.

ABCA1 is a cell-membrane lipid pump that transports cholesterol and other phospholipids out of the cell and onto apolipoproteins such as ApoA-I and ApoE. Some genomewide association studies have tied single-nucleotide polymorphisms in Abca1 to AD (see Wollmer et al., 2003), though others have not seen the association (see ARF related news story on Li et al., 2004).

In mice, Koldamova's group and others have shown that deleting the Abca1 gene exacerbates Aβ deposition in transgenic lines (see ARF related news story), while Abca1 hemizygosity worsens memory problems (see Lefterov et al., 2009). What's more, Abca1 overexpression prevents the AD phenotype in APP transgenic mice (see ARF related news story). These results apply only to mice that express endogenous ApoE; therefore, Koldamova and colleagues wanted to test what happens in mice that express either human ApoE3 or ApoE4. "Our prediction was that deficiency of one Abca1 copy would be equally damaging to both ApoE genotypes," said Koldamova. "This appears not to be the case."

First authors Nicholas Fitz and Andrea Cronican crossed APP-PS1 transgenic mice with human ApoE3 (ARF related news story) or ApoE4 (ARF related news story)-targeted replacement mice, and then bred progeny with Abca1+/- animals. To characterize the APP-PS1/ApoE/Abca1+/- offspring, the researchers tested cognition and measured plaque levels in the brain, as well as various factors in the brain’s interstitial fluid (ISF) and plasma.

To their surprise, the authors found that halving the normal amount of ABCA1 only affected mice with ApoE4, but not those with ApoE3. APP-PS1/E4 mice lacking a copy of Abca1 performed worse than homozygous controls in the radial water maze test. Immunohistochemical staining revealed more numerous compact and diffuse plaques in brains of E4 mice compared to E3 controls. The pattern continued in the interstitial fluid, where shortage of ABCA1 both elevated ISF Aβ42 and Aβ40 and slowed its clearance in ApoE4 mice only. ApoE and ApoA-I levels also fell in soluble brain fractions and in plasma of E4 mice. Finally, levels of high-density lipoproteins and Aβ42 and Aβ40 fell in the plasma of ApoE4 mice, which correlated with more brain plaques.

Why would an ABCA1 deficiency affect ApoE4 carriers more profoundly than ApoE3 mice? It may have to do with how much ApoE there is in the animals, said Koldamova. "ApoE4 mice make less of the protein, so a deficiency of ABCA1 hits them harder than the E3 genotype," she said. If ABCA1 is not around to lipidate apolipoproteins, they become unstable and are metabolized. Because ApoE3 carriers have more of the protein, they may be more resilient to such losses. It is possible that the same differential outcomes would hold true in humans, she added, but that has not been examined yet.

"As we develop therapeutics that target ABCA1 and ApoE, we need to understand whether there are differential effects of ApoE4 versus ApoE3," said David Holtzman, Washington University in St. Louis, Missouri. Holtzman found the ApoE4-specific effects unexpected. Researchers will want to know if a person’s ApoE genotype causes a particular response to liver X receptor (LXR) or retinoic X receptor (RXR) agonists, which elevate ABCA1 and ApoE levels and are currently under investigation as AD treatments, he added (see ARF related news story).

The study hinted that there may be more to exacerbated amyloid pathology than loss of ApoE. In particular, the authors also found that lower plasma high-density lipoproteins (HDLs) correlated with higher plaque levels in the brain in the ApoE4 mice. However, both Landreth and Holtzman agreed that those results were correlational, and that more evidence would be needed to show causation.

Landreth noted that Koldamova and colleagues measured ApoA-I, a component of HDLs, in the brain as well, although the protein is thought to be sequestered in the periphery. Brain ApoA-I fell in E4 Abca1 hemizygotes. "That's a potentially important finding," said Landreth. "If brain levels of ApoA-I can be modulated, then you've got another player in Aβ homeostasis that we didn't think was active."

Koldamova's group will next test the effects of LXR and RXR agonists in Abca1 hemizygotes to see how mice with different ApoE genotypes respond. She also plans to examine the response to other brain insults, such as neurotrauma. Since ApoE carries cholesterol, which is important for synaptic plasticity, axonal regeneration, and cell death, a drop in ABCA1 could compromise injury responses for people with ApoE4.—Gwyneth Dickey Zakaib

Comments

  1. This study by Fitz et al. nicely shows how different ApoE phenotypes may affect amyloid and Aβ levels in the brains of elderly and AD patients. Here, they highlight a direct correlation of human ApoE4 expression and mouse ABCA1 function as a prerequisite for higher cerebral amyloid levels and behavioral abrogation. The investigations show that the effects are controlled by hApoE4 but not by hApoE3. More interestingly, the effect is exacerbated when the mice partially lack mABCA1 expression (heterozygote condition). Whether the genomic heterozygosity also affects mABCA1 kinetics in the animals was unfortunately not shown. Also, compensational mechanisms, for example, upregulation of other ABCA family members would be of interest for investigations. Additionally, one may ask whether there is also any role for LRP1/RAGE or other ABC transporter family members in this effect.

    Nevertheless, the work nicely confirms the functional links between serum proteins and cerebral ABC transporters. This large superfamily of proteins recently came into focus in AD research when it was shown that ABCB1 and ABCC1 can actively excrete Aβ from the brain (1). These and other superfamily members also share important functions in neuronal stem/progenitor cell proliferation and differentiation (2). Moreover, recent GWAS and cerebral tissue investigations detected ABCA7 as a new target of AD research (3,4). And, finally, the regulation of amyloid levels by mitochondrial polymorphisms and different ATP levels that also change ABC transporter function has been highlighted in mouse models (5).

    The future will show whether the ABC transporters and their blood-brain barrier function can explain how sporadic AD may evolve. The recent data are promising and open a wide gate for the development of new drugs.

    References:

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    Allen M, Zou F, Chai HS, Younkin CS, Crook J, Pankratz VS, Carrasquillo MM, Rowley CN, Nair AA, Middha S, Maharjan S, Nguyen T, Ma L, Malphrus KG, Palusak R, Lincoln S, Bisceglio G, Georgescu C, Schultz D, Rakhshan F, Kolbert CP, Jen J, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Schellenberg GD, , Petersen RC, Graff-Radford NR, Dickson DW, Younkin SG, Ertekin-Taner N. Novel late-onset Alzheimer disease loci variants associate with brain gene expression. Neurology. 2012 Jul 17;79(3):221-8. PubMed.

    Scheffler K, Krohn M, Dunkelmann T, Stenzel J, Miroux B, Ibrahim S, von Bohlen und Halbach O, Heinze HJ, Walker LC, Gsponer JA, Pahnke J. Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis. Acta Neuropathol. 2012 Aug;124(2):199-208. PubMed.

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References

News Citations

  1. ABCA1 Links Cholesterol and ApoE, But It May Not Be a Risk Factor for AD
  2. ABCA1 Loss Lowers ApoE, Not Amyloid; New ApoE Immunology
  3. Upping Brain ApoE, Drug Treats Alzheimer's Mice
  4. Putting the Squeeze on Vascularization—A Link Between Cancer and Aβ?
  5. ApoE4 Makes Blood Vessels Leak, Could Kick Off Brain Damage

Paper Citations

  1. Wollmer MA, Streffer JR, Lütjohann D, Tsolaki M, Iakovidou V, Hegi T, Pasch T, Jung HH, Bergmann K, Nitsch RM, Hock C, Papassotiropoulos A. ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer's disease. Neurobiol Aging. 2003 May-Jun;24(3):421-6. PubMed.
  2. Li Y, Tacey K, Doil L, van Luchene R, Garcia V, Rowland C, Schrodi S, Leong D, Lau K, Catanese J, Sninsky J, Nowotny P, Holmans P, Hardy J, Powell J, Lovestone S, Thal L, Owen M, Williams J, Goate A, Grupe A. Association of ABCA1 with late-onset Alzheimer's disease is not observed in a case-control study. Neurosci Lett. 2004 Aug 19;366(3):268-71. PubMed.
  3. Lefterov I, Fitz NF, Cronican A, Lefterov P, Staufenbiel M, Koldamova R. Memory deficits in APP23/Abca1+/- mice correlate with the level of Aβ oligomers. ASN Neuro. 2009;1(2) PubMed.

External Citations

  1. APP-PS1 transgenic mice
  2. Abca1+/- animals

Further Reading

Papers

  1. Karasinska JM, Rinninger F, Lütjohann D, Ruddle P, Franciosi S, Kruit JK, Singaraja RR, Hirsch-Reinshagen V, Fan J, Brunham LR, Bissada N, Ramakrishnan R, Wellington CL, Parks JS, Hayden MR. Specific loss of brain ABCA1 increases brain cholesterol uptake and influences neuronal structure and function. J Neurosci. 2009 Mar 18;29(11):3579-89. PubMed.
  2. Rodríguez-Rodríguez E, Mateo I, Llorca J, Sánchez-Quintana C, Infante J, García-Gorostiaga I, Sánchez-Juan P, Berciano J, Combarros O. Association of genetic variants of ABCA1 with Alzheimer's disease risk. Am J Med Genet B Neuropsychiatr Genet. 2007 Oct 5;144B(7):964-8. PubMed.
  3. Koldamova R, Lefterov I. Role of LXR and ABCA1 in the pathogenesis of Alzheimer's disease - implications for a new therapeutic approach. Curr Alzheimer Res. 2007 Apr;4(2):171-8. PubMed.
  4. Wollmer MA, Streffer JR, Lütjohann D, Tsolaki M, Iakovidou V, Hegi T, Pasch T, Jung HH, Bergmann K, Nitsch RM, Hock C, Papassotiropoulos A. ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer's disease. Neurobiol Aging. 2003 May-Jun;24(3):421-6. PubMed.

Primary Papers

  1. Fitz NF, Cronican AA, Saleem M, Fauq AH, Chapman R, Lefterov I, Koldamova R. Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J Neurosci. 2012 Sep 19;32(38):13125-36. PubMed.

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