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:
1. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, Steffen J, Schumacher T, Brüning T, Plath AS, Alfen F, Schmidt A, Winter F, Rateitschak K, Wree A, Gsponer J, Walker LC, Pahnke J. Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice. J Clin Invest. 2011 Oct;121(10):3924-31. Abstract
2. Schumacher T, Krohn M, Hofrichter J, Lange C, Stenzel J, Steffen J, Dunkelmann T, Paarmann K, Fröhlich C, Uecker A, Plath AS, Sommer A, Brüning T, Heinze HJ, Pahnke J. ABC transporters B1, C1 and G2 differentially regulate neuroregeneration in mice. PLoS One. 2012;7(4):e35613. Abstract
3. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Rüther E, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Gallacher J, Hüll M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, Alzheimer's Disease Neuroimaging Initiative, van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, CHARGE Consortium, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alpérovitch A, Lathrop M, EADI1 Consortium, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snædal J, Björnsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossù P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O'Donovan M, Amouyel P, Williams J. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011 May;43(5):429-35. Abstract
4. 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, Alzheimer's Disease Genetics Consortium, 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. Abstract
5. 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. Abstract
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