24-Hydroxycholesterol is a natural sterol, which serves as a positive allosteric modulator of N-Methyl-d-Aspartate (NMDA) receptorsR, and a potent activator of the transcription factors LXR.
24S-hydroxycholesterol oxysterol-generating enzyme Cyp46a1 is overexpressed during the angiogenic switch in rat insulin promoter 1-T-antigen 2 (RIP1-Tag2) pNET formation[1].
Hypoxia inducible factor-1a (HIF-1α) controls the overexpression of the enzyme Cyp46a1, which generates the oxysterol 24-hydroxycholesterol in a pancreatic neuroendocrine tumor (pNET) model commonly used to study neoangiogenesis. The activation of the HIF-1α-24S-HC axis ultimately leads to the induction of the angiogenic switch through the positioning of proangiogenic neutrophils in proximity to Cyp46a1+ islets[1]. 24-hydroxycholesterol levels are increased at 2-4 months in the untreated 5XFAD mouse brain and then became similar to those in the B6SJL mouse brain[2].
[1]. Soncini M, et al. 24-Hydroxycholesterol participates in pancreatic neuroendocrine tumor development. Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6219-E6227. Epub 2016 Sep 26. [2]. Mast N, et al. Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease. Neuropharmacology. 2017 Sep 1;123:465-476.