Identification and modification of amyloid-independent phenotypes of APOE4 mice

Abstract

Background Over 70 million Americans inherit the strongest genetic risk factor for Alzheimer’s disease (AD), apolipoprotein E4 (APOE4), but have no course for reducing their risk. The association of non-steroidal anti-inflammatory drug (NSAID) use with reduced risk of AD for APOE4-carriers suggests that NSAIDs may be useful in AD prevention. Methods We identified phenotypes associated with APOE4 in APOE knock-in mice in order to define modifiable measures that correlate with risk of AD. Results APOE4 mouse brains showed altered post-translational modifications and biochemical distribution of APOE compared to APOE3 mice; these differences were also observed in brains of human APOE4 carriers. Two-month treatment with ibuprofen significantly altered the expression pattern of APOE in APOE4 mice to that of APOE3 mice; PPAR-γ agonist pioglitazone also had a significant effect. APOE4 mice also show deficits in dendritic spine density, and ibuprofen and pioglitazone significantly increased dendritic spine density. Conclusions We report new phenotypes associated with APOE4 in control human and APOE knock-in mice and their mitigation with NSAID treatment, through COX-2 inhibition and PPAR-γ activation.

Geroprotective and Radioprotective Activity of Quercetin, (-)-Epicatechin, and Ibuprofen in Drosophila melanogaster

“…Their inhibition at the middle age using ibuprofen can cause the pronounced life extending effect that we observed in the present study. Additionally, ibuprofen can regulate the activity of the protein apolipoprotein E that associated with the neurodegenerative processes in mammalian brain, including development of Alzheimer's and Parkinson's diseases, through the COX-2 inhibition and PPAR-γ activation (Melton et al, 2003; Lichtenstein et al, 2010; DiBattista et al, 2016). Investigations on transgenic fruit flies demonstrated that this effect can influence the lifespan and aging rate (Lichtenstein et al, 2010).…”

The role of APOE on lipid homeostasis and inflammation in normal brains

“…We have identified biochemical differences in modified versions of brain APOE: unmodified APOE is solubilized only in the presence of detergent and modified APOE is solubilized in saline (65). The ratio of these different forms is altered by APOE genotypes in mouse and human brains (65). The APOE isoform effects on APOE levels and on dimer formation support lossof-function explanations for the effects of APOE4, with APOE4 less able to clear debris and deliver lipids than APOE2 or APOE3.…”

“…Finally, the APOE protein is modified by O-glycosylation (64), and to a greater extent in the CNS than in the periphery (26). We have identified biochemical differences in modified versions of brain APOE: unmodified APOE is solubilized only in the presence of detergent and modified APOE is solubilized in saline (65). The ratio of these different forms is altered by APOE genotypes in mouse and human brains (65).…”

“…APOE genotype affects a number of CNS phenotypes in young individuals, as demonstrated both in mice and in humans (65). APOE4 knock-in mice have several differences compared with APOE3 mice.…”

APOE2promotes longevity independent of Alzheimer’s disease

“…We thus analyzed human apoE-targeted replacement (apoE-TR) (12)(13)(14) and Apoe-knockout (15) mice to examine whether the effects of APOE on lifespan can indeed be observed in the absence of AD. In the absence of overexpressing mutant APP or mutant MAPT gene, these mice do not display remarkable amyloid or tau deposition such as those seen in AD (10,19,20). In the survival mouse cohort (n=118), due to the regulation of our animal experiment, we euthanized mice (33.9% of total animals) when they showed severe age-related symptoms including severe weakness, masses, significant skin lesions etc.…”