ApoE4 and its fragments impair mitochondrial function
Mitochondrial dysfunction has been reported in AD, which is modulated by apoE genotype, with a greater effect in apoE4 than in apoE3 carriers [121-124,125]. In both AD patients and age-matched nondemented subjects, apoE4 is associated with decreased cerebral glucose metabolism [126-135], an effect that occurs decades before cognitive impairment become apparent [126,127,136] and, probably, also before significant Aβ deposition. Thus, apoE4 may cause mitochondrial dysfunction at very early stages in life. Mitochondrial dysfunction is clearly coupled with production of reactive oxygen species and increased oxidative damage, which in turn further impair mitochondrial activity. Temporary or sustained loss of mitochondrial function impairs cellular defenses and repair mechanisms, decreasing the ability of neurons to mount an appropriate stress response and causing cellular injury.
The mitochondrial metabolism study on the young apoe4s was a very small sample.
Biophysical studies suggest that the lipid-binding domain within the C-terminal-truncated apoE4 has a less organized structure and greater exposure of the hydrophobic residues than full-length apoE4 [142,143], which might increase the interaction with mitochondrial membrane. Interestingly, almost 20 years ago, it was found that apoE avidly bound to mitochondrial ATPase . In addition, small amounts of apoE have been identified in hepatocyte mitochondria . Blocking the interaction of apoE4 fragments with mitochondria might prevent the detrimental effects on mitochondria function, and increasing the activity or number of mitochondria in neurons might also eliminate the detrimental effect of apoE4 fragments (Figure 2).
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