Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Inheritance of the apoE4 allele (epsilon 4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of epsilon 4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of epsilon 2/2, epsilon 3/3, and epsilon 4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; epsilon 2/2 > epsilon 3/3 > epsilon 4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the epsilon 3/4 mouse brains. ApoE4 represented 30-40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between epsilon 3/3 and epsilon 3/4 mice, implying that the reduced levels of total apoE in epsilon 3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from epsilon 3/4 human astrocytoma or epsilon 3/3, epsilon 4/4 and epsilon 3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from epsilon 4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by epsilon 4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or A beta clearance.