Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer's transgenic mice.J Alzheimers Dis 2010; 20 Suppl 2:S535-50JA
Mitochondrial dysfunction is observed in Alzheimer's disease (AD) brain, and the amyloid-beta (Abeta) peptide is known to induce mitochondrial dysfunction. The relative degree of mitochondrial dysfunction in different regions of the brain in AD is not completely understood. Moreover, the relationship between levels of synaptic mitochondrial Abeta and mitochondrial dysfunction has not been clearly established. Therefore synaptic and nonsynaptic mitochondria were isolated from the hippocampus, cortex, striatum, and amygdala of 12 month AbetaPPsw and AbetaPP+PS1 mouse models of AD as well as nontransgenic mice. Mitochondrial respiratory rates, reactive oxygen species production, membrane potential, and cytochrome c oxidase activity were measured. Hippocampal and cortical mitochondria showed the highest levels of mitochondrial dysfunction, while striatal mitochondria were moderately affected, and amygdalar mitochondria were minimally affected. Mitochondria from AbetaPP/PS1 brain regions were more impaired than those from AbetaPP mice. Mitochondrial Abeta levels nearly mirrored the extent of mitochondrial dysfunction. Synaptic mitochondria were more impaired than nonsynaptic mitochondria in the AD mouse models. The AbetaPP/PS1 mice showed more impairment in the cognitive interference task of working memory than the AbetaPP mice. The association between mitochondrial Abeta levels and mitochondrial dysfunction in mouse models of AD supports a primary role for mitochondrial Abeta in AD pathology. Moreover, the degree of cognitive impairment in AD transgenic mice can be linked to the extent of synaptic mitochondrial dysfunction and mitochondrial Abeta levels, suggesting that a mitochondrial Abeta-induced signaling cascade may contribute to cognitive impairment. Therapeutics that target this cascade could be beneficial in the treatment of AD.