395 – Brain lipidology: understanding APOE, cholesterol homeostasis, Alzheimer’s disease, & more
In a Nutshell
The brain produces and manages all its own cholesterol independently of plasma levels, using astrocytes to synthesize it and APOE-containing HDL-like particles to deliver it to neurons via the matriosome. APOE4 impairs this delivery, disrupts membrane cholesterol balance, and increases amyloid-beta 42 production, elevating Alzheimer's risk, while excess neuronal cholesterol is eliminated as 24S-hydroxycholesterol. Statins and CETP inhibitors can modulate brain cholesterol synthesis and enhance protective apoA1 transport across the blood-brain barrier, respectively, offering potential therapeutic avenues when monitored via desmosterol and oxysterol biomarkers.
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Peter Attia welcomes Tom Dayspring back to discuss cholesterol in the brain, noting this has become an enormous passion and area of curiosity. They begin with foundational knowledge about lipids to ensure everyone starts from the same baseline.
Cholesterol is essential for human life and is used for making critical molecules, but its most important function is positioning itself in cell membranes throughout the body. Cell membranes regulate integrity and control what enters and exits cells. Evolution has given every cell in the body the ability to de novo synthesize the cholesterol it needs. Each cell needs only a minor number of cholesterol molecules, but if a cell over-synthesizes or accumulates excess cholesterol, the cholesterol can crystallize, which is toxic to the cell and will kill it.
Evolution has given cells the ability to export excess cholesterol out of the cytosol into plasma. However, lipids are hydrophobic and cannot circulate freely in plasma, which is an aqueous solution. Evolution solved this by providing proteins that bind to lipids and wrap them into particles called lipoproteins, allowing lipids including cholesterol and triglycerides to circulate in the bloodstream.
When a cell fluxes cholesterol out, it joins with a protein called APOA1, the structural protein of high-density lipoproteins (HDLs). HDLs accept cholesterol from any cell in the body that is effluxing it. The apoB family of lipoproteins are much bigger than HDLs and are produced in the liver, with one type produced in the small intestine. The structural protein of apoB lipoproteins is the very large peptide called apolipoprotein B.
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