Mechanistic description
A more conjectural model is that APOE4-driven lipid remodeling changes ER membrane organization so that SCAP perceives cholesterol insufficiency at a given sterol mass. This is conceptually interesting and compatible with accessible-cholesterol biology, but currently lacks direct APOE4-specific evidence and remains below funding priority.
Evidence for (7)
SCAP responds to the accessible cholesterol fraction in ER membranes rather than simply total cholesterol mass.
APOE4 causes broad intracellular lipid-trafficking abnormalities that could plausibly alter membrane composition.
The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER-Golgi membrane contact sites.
Dysfunction of cholesterol sensor SCAP promotes inflammation activation in THP-1 macrophages.
Control of innate immunity and lipid biosynthesis in neurodegeneration.
SCAP, an ER sensor that regulates cell cholesterol.
Assaying Sterol-Regulated ER-to-Golgi Transport of SREBP Cleavage-Activating Protein Using Immunofluorescence Microscopy.
Evidence against (3)
No direct evidence links APOE4 to a shifted SCAP cholesterol threshold in ER membranes.
Apparent changes in accessible cholesterol could instead reflect altered sterol mass, probe artifacts, or generalized membrane stress.
Interventions such as SOAT1/ACAT1 modulation are broad and may perturb lipid droplets, ER stress responses, and myelination.