Cholesterol and ApoE

High Cholesterol Level Increases Ab Production

Dozens of reports have confirmed that cholesterol-lowering drugs such as statins can decrease the risk of Alzheimer's disease (AD).  It was further shown that low cholesterol reduces the production of beta amyloid (Ab). The underlying mechanism has been elucidated.

The beta amyloid is generated from its precursor protein (APP) by two enzymatic cleavages: b-secretase cuts APP at a position outside the cell and  g-secretase cuts APP at a position inside the cell membrane (more info). The g-secretase site is unusual because it is located in the membrane. The intramembrane catalysis requires a domain structure called "lipid raft" which is rich in cholesterol (figure). Therefore, higher cholesterol level favors the formation of lipid rafts, thereby increasing the production of beta amyloid.

The effects of ApoE on Ab

Apolipoprotein E (apoE) is a protein with 299 amino acids. Its gene is located on chromosome 19. The gene is polymorphic [i.e., having several variants (alleles)] with three alleles, encoding three protein isoforms: apoE2, apoE3, and apoE4. Their frequencies in populations are 5-10%, 60-70%, and 15-20%, respectively (reference). People with apoE4 are more likely to develop Alzheimer's disease.

Apolipoprotein E (apoE) is important for removing excess cholesterol from the blood, and does so by carrying cholesterol to receptors on the surface of liver cells. Defects in apoE sometimes result in its inability to bind to the receptors, which leads to an increase in a person's blood cholesterol and consequently their risk of atherosclerosis.

In the central nervous system (CNS), ApoE is produced by astrocytes, activated microglia, and neurons. The role of apoE is to redistribute lipid (including cholesterol) among CNS cells. Since cholesterol is involved in the development of AD, the finding that apoE4 is a risk factor for AD might result from its function as a cholesterol transport protein. However, experiments do not support this idea.

ApoE has been shown to affect beta amyloid in several ways. It can bind to Ab, thereby inhibiting its clearance and stimulating its deposition. The apoE4 binds to Ab more rapidly than apoE3. ApoE can also increases Ab production, but apoE4 stimulates Ab production more effectively than apoE3 (reference).

References:

National Institute on Aging, USA

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease - PNAS, 2006.