A 40-year-old African American man was referred to the Lipid Clinic, University of California, San Francisco, with severe hyperlipidemia relatively unresponsive to statin and fibrate treatment. He had large tuberous xanthomas ... His diet, generally low in fat, contained little saturated and no trans fats and was low in rapidly absorbed carbohydrates. He had no signs or symptoms of neurological deficit, ophthalmological disease, or cardiovascular disease (CVD). He did not start talking until age 3 years. At school, he performed better in mathematics than reading, finishing 11th grade with a C+/B− average. ... [He underwent] Whole-exome sequencing, lipoprotein analysis, and neurocognitive function.
Results The patient was homozygous for an ablative APOE frameshift mutation (c.291del, p.E97fs). [That is: the mutation caused him to produce zero APOE, of any flavor -M]. ... Despite complete absence of apoE, he had normal vision, exhibited normal cognitive, neurological, and retinal function, had normal findings on brain magnetic resonance imaging, and had normal cerebrospinal fluid levels of β-amyloid and tau proteins. He had no significant symptoms of cardiovascular disease except a suggestion of myocardial ischemia on treadmill testing and mild atherosclerosis noted on carotid ultrasonography. He had exceptionally high [serum] cholesterol content [and various unusual lipid characteristics] ...
Conclusions and Relevance Despite a profound effect on lipoprotein metabolism, detailed neurocognitive and retinal studies failed to demonstrate any defects. This suggests that functions of apoE in the brain and eye are not essential or that redundant mechanisms exist whereby its role can be fulfilled.
JAMA Neurol. 2014;71(10):1228-1236. doi:10.1001/jamaneurol.2014.2011
Good question!Do you know why PH002 itself isn't a therapy?
ApropoE4 wrote:I wouldn't give mice PH002 unless I want to kill them. (actually most of my interactions with mice involved killing them so that might not be a bad thing).
Why do you assume that?but without the toxic effects that I assume PH002 would have on mice and men
However, to date, the most potent phthalazinone apoE4SCs caused significant toxicity in mice. Therefore, we have expanded our validation studies to other apoE4SCs. A series of pyrazoline analogues were prepared by Merck Research Laboratories and used to establish SARs. This series was highly effective in blocking apoE4 domain interaction, as determined by FRET, and demonstrated parallel effects in enhancing COX1 levels and reducing mitochondrial toxicity in apoE4-expressing neuronal cells.
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