2 research outputs found
Macrophage-Specific ApoE Gene Repair Reduces Diet-Induced Hyperlipidemia and Atherosclerosis in Hypomorphic Apoe Mice
Apolipoprotein (apo) E is best known for its ability to lower plasma cholesterol and protect against atherosclerosis. Although the liver is the major source of plasma apoE, extra-hepatic sources of apoE, including from macrophages, account for up to 10% of plasma apoE levels. This study examined the contribution of macrophage-derived apoE expression levels in diet-induced hyperlipidemia and atherosclerosis.Hypomorphic apoE (Apoe(h/h)) mice expressing wildtype mouse apoE at âŒ2-5% of physiological levels in all tissues were derived by gene targeting in embryonic stem cells. Cre-mediated gene repair of the Apoe(h/h) allele in Apoe(h/h)LysM-Cre mice raised apoE expression levels by 26 fold in freshly isolated peritoneal macrophages, restoring it to 37% of levels seen in wildtype mice. Chow-fed Apoe(h/h)LysM-Cre and Apoe(h/h) mice displayed similar plasma apoE and cholesterol levels (55.53±2.90 mg/dl versus 62.70±2.77 mg/dl, nâ=â12). When fed a high-cholesterol diet (HCD) for 16 weeks, Apoe(h/h)LysM-Cre mice displayed a 3-fold increase in plasma apoE and a concomitant 32% decrease in plasma cholesterol when compared to Apoe(h/h) mice (602.20±22.30 mg/dl versus 888.80±24.99 mg/dl, nâ=â7). On HCD, Apoe(h/h)LysM-Cre mice showed increased apoE immunoreactivity in lesional macrophages and liver-associated Kupffer cells but not hepatocytes. In addition, Apoe(h/h)LysM-Cre mice developed 35% less atherosclerotic lesions in the aortic root than Apoe(h/h) mice (167Ă10(3)±16Ă10(3) ”m(2) versus 259Ă10(3)±56Ă10(3) ”m(2), nâ=â7). This difference in atherosclerosis lesions size was proportional to the observed reduction in plasma cholesterol.Macrophage-derived apoE raises plasma apoE levels in response to diet-induced hyperlipidemia and by such reduces atherosclerosis proportionally to the extent to which it lowers plasma cholesterol levels
Small-Molecule Structure Correctors Target Abnormal Protein Structure and Function: Structure Corrector Rescue of Apolipoprotein E4âAssociated Neuropathology
An attractive strategy to treat proteinopathiesâdiseases caused by malformed or misfolded proteinsâis to restore protein function by inducing proper three-dimensional structure. We hypothesized that this approach would be effective in reversing the detrimental effects of apolipoprotein (apo) E4, the major allele that significantly increases the risk of developing Alzheimerâs disease and other neurodegenerative disorders. ApoE4âs detrimental effects result from its altered protein conformation (âdomain interactionâ), making it highly susceptible to proteolytic cleavage and the generation of neurotoxic fragments. Here, we review apoE structure and function, how apoE4 causes neurotoxicity, and describe the identification of potent small-molecule-based âstructure correctorsâ that induce proper apoE4 folding. SAR studies identified a series of small molecules that significantly reduced apoE4âs neurotoxic effects in cultured neurons, and a series that reduced apoE4 fragment levels in vivo, providing proof-of-concept for our approach. Structure correctorâbased therapies could prove highly effective for the treatment of many protein-misfolding diseases