. 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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  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:

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

    . ABC transporters B1, C1 and G2 differentially regulate neuroregeneration in mice. PLoS One. 2012;7(4) Epub 2012 Apr 24 PubMed.

    . 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.

    . Novel late-onset Alzheimer disease loci variants associate with brain gene expression. Neurology. 2012 Jul 17;79(3):221-8. PubMed.

    . Mitochondrial DNA polymorphisms specifically modify cerebral β-amyloid proteostasis. Acta Neuropathol. 2012 Aug;124(2):199-208. PubMed.

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