Cholesterol is an essential fatty substrate of cells and is produced de novo in the central nervous system. The regulation of cholesterol in cells for biogenesis and export is tightly regulated and mainly required for cell membrane formation and maintenance, metabolic and immunological processes.

Cholesterol regulation in a snapshot: When intracellular cholesterol increases and reaches a certain threshold, cholesterol is esterified into cholesteryl esters which are stored in  lipid droplets. Contrary, when cells sense low cholesterol, esterified cholesterol can be transported by lipidated proteins such as APOE to be converted back to cholesterol and used in cellurar membranes and processes.  

We have previously shown that accumulation of cholesterol esters in neurons impairs proteasomal degradation of phosphorylated Tau (Cell Stem Cell paper, comment, Alzforum link). Based on these findings we initiated a phase 2a clinical trial with low-dose Efavirenz as a brain-cholesterol lowering drug. 

We have a number of active projects aimed to understanding the mechanisms by which cholesterol lowering drugs and other candidate drugs regulate the proteasome. In addition, we are investigating how APP, APP processing and APP mutations affect cholesterol metabolism and vice versa. We also investigate how ApoE4, and Tau mutations, affect neuronal lipid metabolism. 

Lab Members  Involved 

• Almudena | Tom | Iris  | Jorin | Marina | Position opening autumn 2024