Reducing Human Apolipoprotein E Levels Attenuates Age-Dependent Aβ Accumulation in Mutant Human Amyloid Precursor Protein Transgenic Mice

Abstract

Apolipoprotein (apo) E4 plays a major role in the pathogenesis of Alzheimer’s disease (AD). Brain amyloid-beta (Aβ) accumulation depends on age and apoE isoforms (apoE4 > apoE3) both in humans and in transgenic mouse models. Brain apoE levels are also isoform-dependent, but in the opposite direction (apoE4 < apoE3). Thus, one prevailing hypothesis is to increase brain apoE expression to reduce Aβ levels. To test this hypothesis, we generated mutant human amyloid precursor protein (hAPP) transgenic mice expressing one or two copies of the human apoE3 or apoE4 gene that was knocked-in and flanked by LoxP sites. We report that reducing apoE3 or apoE4 expression by 50% in 6-month-old mice results in efficient Aβ clearance and does not increase Aβ accumulation. However, 12-month-old mice with one copy of the human apoE gene had significantly reduced Aβ levels and plaque loads compared to mice with two copies, regardless of which human apoE isoform was expressed, suggesting a gene dose-dependent effect of apoE on Aβ accumulation in aged mice. Additionally, 12-month-old mice expressing one or two copies of the human apoE4 gene had significantly higher levels of Aβ accumulation and plaque loads than age-matched mice expressing one or two copies of the human apoE3 gene, suggesting an isoform-dependent effect of apoE on Aβ accumulation in aged mice. Moreover, Cre-mediated apoE4 gene excision in hippocampal astrocytes significantly reduced insoluble Aβ in adult mice. Thus, reducing, rather than increasing, apoE expression is an attractive approach to lowering brain Aβ levels.

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

“…Interestingly, APP Tg mice expressing only one copy of human apoE have significantly less A plaque deposition compared with mice expressing two copies of the same apoE isoform (either APOE-3 or APOE-4) (84). Very similar findings were also found by another group (85), and have potentially important therapeutic implications because there has been a long debate about whether increasing or decreasing apoE is beneficial for A pathology. The caveat of these findings is that the animals carried the APOE gene and gene dosage differences since birth, and there could be developmental compensation in the genetic APOE haploinsufficiency model that could account for the protective effect against A deposition.…”

APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease

“…This suggests that any observed APOE genotype-specific differences in A␤ accumulation are not mediated by altered APP expression or processing. These results are consistent with results from the PDAPP/apoE-TR mice (3) and J20/APOEfKI (45) where no significant differences in APP levels were observed with the APOE genotype.…”

Systems genetics identifies modifiers of Alzheimer’s disease risk and resilience

“…This suggests that while more Apoe is overall detrimental to learning, this effect is exacerbated when the D allele of Apoe is present. Similar allele-specific results have been observed when over-expressing human APOE in transgenic mice (Bien-Ly et al, 2012). Interestingly, the D allele harbors only a single SNP when compared to the B6 allele, and this missense mutation causes the D2 sequence to match the human ε4 variant more closely than the B6 sequence ( Figure 3H).…”