20 October 2005. A foursome of papers on ApoE deserves attention this week. Having plenty of ApoE is a prerequisite for amyloid deposition in mouse models of Alzheimer disease—just look at the ApoE knockout, whose offspring manage to maintain a clean cortex and plaque-free hippocampus even when bred to AD-prone mates. Keeping brain ApoE levels high is the province of the ABCA1 (ATP binding cassette transporter A1) protein, which shuttles cholesterol out of cells and loads it onto ApoE. There has been some suggestion that the ABCA1 alleles may be associated with late-onset AD, and the observation that ABCA1 knockouts have dramatically lower levels of ApoE in their CNS led to the suggestion that this protein might be a useful therapeutic target in AD (see ARF related news story).
That idea may need revision in light of three new papers showing the results of crossing ABCA1-deficient mice with four different strains of AD mice. Through all of the models the results are consistent: Loss of ABCA1 decreases soluble ApoE dramatically (as expected), but this decrease is accompanied by an increase in amyloid deposition, and this was a surprise. While the mechanism of this enhancement is unclear, it may be driven by the accumulation of poorly lipidated, insoluble ApoE that ultimately turns up in plaques.
All three ABCA1 papers are in press in the Journal of Biological Chemistry and available online. Two are from the labs of David Holtzman at Washington University in St. Louis and Cheryl Wellington at the University of British Columbia in Vancouver, both of whom had previously characterized ApoE in the CNS of the ABCA1 knockouts. The third entry is the work of Radosveta Koldamova and Iliyal Lefterov of the University of Pittsburg, along with a collaborator from Novartis in Basel.
And keeping the spotlight on the "lipo" in apolipoprotein E is a new and unexpected finding from immunologist Michael Brenner and colleagues at Harvard Medical School, who showed that ApoE can function as a delivery system to bring lipid antigens to the immune system. Whether this new immune function plays any role in AD remains to be seen, but the results surely will have many researchers looking at ApoE in a new light.
To evaluate the impact of ABCA1 on amyloid processing and deposition, three different groups crossed ABCA1-knockout mice with four different strains of AD mice. When they looked in the brain, APP levels and the production of Aβ peptides were unchanged. But contrary to expectations, in three of the four model strains, amyloid load, whether measured as insoluble Aβ, thioflavin-positive plaques, or as histochemistry, was increased, while in one it remained the same. In the most dramatic case, amyloid burden was increased about twofold.
All the mice showed a substantial reduction in soluble ApoE, consistent with the phenotype of the parent ABCA1 knockouts. For the most part, the researchers demonstrated a higher fraction of ApoE in the insoluble material, and two of the groups showed that insoluble ApoE accumulated in amyloid plaques.
In general, the results all supported the same conclusions: First, while ABCA1 had no role in Aβ production, it appeared to be very important in maintaining ApoE levels in vivo in the brain. Second, the ABCA1-mediated decrease in ApoE failed to reduce amyloid deposition in any of the mouse models. Or, as Wellington and colleagues write, “Three laboratories have now independently demonstrated that amyloid deposition fails to be reduced in four models of AD despite low ApoE levels in the absence of ABCA1, and that these effects extend across differences in the transgene expressed, the mutations it carries, the promoter used, and genetic background of the animals.”
While the reason for the increase is not known, the researchers speculate that the lack of ApoE may hinder the clearance of Aβ, particularly by astrocytes who take up ApoE-containing complexes by receptor-mediated endocytosis. Alternatively, it could be that poor lipidation of ApoE renders it prone to sequestration in amyloid plaques and enhances soluble Aβ to amyloid conversion. When Holtzman and colleagues looked at older mice, they saw insoluble ApoE co-deposited with amyloid and concluded that, even with much lower ApoE levels in the knockout, the poorly lipidated ApoE was strongly amyloidogenic.
As if ApoE physiology wasn’t already complex enough, a paper published in the October 6 issue of Nature adds another aspect to consider. Peter van den Elzen, Michael Brenner, and their colleagues showed that ApoE carries not just dietary lipids, but also ferries lipid-containing antigens into antigen-presenting cells of the immune system, where they are processed and presented to a special class of lipid-reactive T cells. Delivery by ApoE allows cells to efficiently capture antigens via receptor-mediated endocytosis, and facilitates their transfer to CD1 molecules in endocytic vesicles, followed by movement to the cell surface and recognition by T cells. Both CD1 and lipid-reactive T cells have been implicated in several inflammatory and autoimmune diseases, including atherosclerosis. Late-stage AD is marked by inflammation in the brain, and the unexpected confluence between ApoE and immune activation should stimulate a look at the possible role of lipid antigens in the disease.—Pat McCaffrey.
Hirsch-Reinshagen V, Maia LF, Burgess BL, Blain JF, Naus KE, McIsaac SA, Parkinson PF, Chan JY, Tansley GH, Hayden MR, Poirier J, Van Nostrand W, Wellington CL. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer's disease. J Biol Chem. 2005 Oct 5; [Epub ahead of print] Abstract
Koldamova R, Staufenbiel M, Lefterov I. Lack of ABCA1 considerably decreases brain Apoe level and increases amyloid deposition in APP23 mice. J Biol Chem. 2005 Oct 5; [Epub ahead of print] Abstract
Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, Paul SM, Holtzman DM. Deletion of Abca1 increases Aβ deposition in the PDAPP transgenic mouse model of Alzheimer's disease. J Biol Chem. 2005 Oct 5; [Epub ahead of print] Abstract
van den Elzen P, Garg S, Leon L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng TY, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, Brenner MB. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature. 2005 Oct 6;437(7060):906-10. Abstract