Soluble beta-amyloid leads to mitochondrial defects in amyloid precursor protein and tau transgenic mice

Mitochondrial dysfunction has been identified in neurodegenerative disorders including Alzheimer's disease, where accumulation of beta-amyloid (Abeta) and oxidative stress seem to play central roles in the pathogenesis, by probably directly leading to mitochondrial dysfunction.

In order to study the in vivo effect of Abeta load during aging, we evaluated the mitochondrial function of brain cells from transgenic mice bearing either mutant amyloid precursor protein (tgAPP) or mutant amyloid precursor protein and mutant PS1 (tgAPP/PS1) as well as from nontransgenic wild-type littermates. tgAPP mice exhibit onset of Abeta plaques at an age of 6 months, but the intracellular soluble Abeta load is already increased at 3 months of age. In contrast, onset of Abeta plaques starts at an age of 3 months in tgAPP/PS1 mice. In addition, we investigated the effects of different Abeta preparations on mitochondrial function of brain cells from tau transgenic mice.

Of note, mitochondrial damage such as reduced mitochondrial membrane potential and ATP levels can already be detected in the brains from these mice before the onset of plaques. In agreement with our findings in tgAPP mice, soluble Abeta induced mitochondrial dysfunction in brain cells from tau transgenic mice.

Our results indicate that mitochondrial dysfunction is exacerbated by the presence of soluble Abeta species as a very early event during pathogenesis.