Abstract
BackgroundHuman apolipoprotein E (apoE) exists in three major isoforms: apoE2, apoE3 and apoE4. In the brain, apoE is produced mostly by astrocytes and transports cholesterol to neurons via apoE receptors. Among the gene alleles encoding the three isoforms, the APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), whereas APOE2 is protective. ApoE4 confers a gain of toxic function, a loss of neuroprotective function or a combination of both in AD pathogenesis. Given that therapeutic impacts of modulating apoE expression may be isoform-dependent, we sought to investigate the relationship between overexpressing apoE isoform and apoE-related functions in apoE-targeted replacement (TR) mice. Specifically, apoE isoform expression driven by the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter was built into an adeno-associated virus serotype 8 (AAV8) vector and injected into the ventricles of postnatal day 2 (P2) apoE3-TR or apoE4-TR mice. Upon confirmation of apoE isoform expression, effects on apoE lipidation and the levels of amyloid-β (Aβ) in the brain were assessed.ResultsAAV8-GFAP-apoE isoforms were specifically expressed in astrocytes throughout all brain regions, which led to overall increased apoE levels in the brain. Viral mediated overexpression of apoE4 in the apoE4-TR background increased poorly-lipidated apoE lipoprotein particles and decreased apoE-associated cholesterol in apoE4-TR mice. Conversely, apoE2 overexpression in apoE4-TR mice enhanced apoE lipidation and associated cholesterol. Furthermore, overexpression of apoE4 elevated the levels of endogenous Aβ, whereas apoE2 overexpression trended to lower endogenous Aβ.ConclusionsOverexpression of apoE isoforms induces differential effects in the apoE4-TR background: apoE4 decreases apoE lipidation and enhances Aβ accumulation, whereas apoE2 has the opposite effects. Our findings suggest that increasing apoE2 in APOE4 carriers is a beneficial strategy to treat AD, whereas increasing apoE4 in APOE4 carriers is likely harmful. We have also established novel methods to express apoE isoforms in mouse brain to study apoE-related pathways in AD and related dementia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0001-3) contains supplementary material, which is available to authorized users.
Highlights
IntroductionHuman apolipoprotein E (apoE) exists in three major isoforms: apoE2, apoE3 and apoE4
Human apolipoprotein E exists in three major isoforms: apoE2, apoE3 and apoE4
We found that both GFP and apoE isoforms, detected with an HA antibody, were co-localized with GFAPpositive astrocytes, but not with Iba1-positive microglia or NeuN-positive neurons (Figure 1B-E)
Summary
Human apolipoprotein E (apoE) exists in three major isoforms: apoE2, apoE3 and apoE4. Previous studies have shown that brain Aβ levels and amyloid plaque loads are apoE isoform-dependent (E4 > E3 > E2) both in humans and in AD transgenic mouse models [11,12,13]. Liver X receptors (LXRs) or the retinoid X receptor (RXR) agonists facilitate Aβ clearance and reverse the memory deficits in amyloid model mice by increasing apoE levels and its lipidation [18,19,20]. These results suggest that apoE levels and lipidation status likely contribute to Aβ clearance; new therapeutic approaches aimed at increasing apoE expression are actively being pursued. To better design mechanism-based therapy, it is critical to understand how increasing apoE expression, in particular apoE4 in APOE4 carriers, impacts apoE lipidation and Aβ metabolism
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