Inheritance of the
apoE4 allele (epsilon4) increases the risk of developing
Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of epsilon4 may lead to reduced
apoE protein levels in the CNS. We therefore examined
apoE protein levels in the brains, CSF and plasma of epsilon2/2, epsilon3/3, and epsilon4/4 targeted replacement mice. These
apoE mice showed a genotype-dependent decrease in
apoE levels; epsilon2/2 >epsilon3/3 >epsilon4/4. Next, we sought to examine the relative contributions of
apoE4 and
apoE3 in the epsilon3/4 mouse brains.
ApoE4 represented 30-40% of the total
apoE. Moreover, the absolute amount of
apoE3 per allele was similar between epsilon3/3 and epsilon3/4 mice, implying that the reduced levels of total
apoE in epsilon3/4 mice can be explained by the reduction in
apoE4 levels. In culture medium from epsilon3/4 human
astrocytoma or epsilon3/3, epsilon4/4 and epsilon3/4 primary astrocytes,
apoE4 levels were consistently lower than
apoE3. Secreted
cholesterol levels were also lower from epsilon4/4 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 epsilon4 carriers may directly contribute to the
disease progression, perhaps by reducing the capacity of
apoE to promote synaptic repair and/or Abeta clearance.