P2‐077: Early mitochondrial dysfunction in the etiology of Alzheimer's disease

Abstract

The identification of early mechanisms underlying Alzheimer's disease (AD) and associated biomarkers could advance development of new therapies, and improve monitoring and predicting of AD progression. Mitochondrial dysfunction has been suggested to underlie early mechanisms of AD. However, no comprehensive study exists that evaluate the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain metabolomics. We characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. Mitochondrial trafficking was examined in live neurons form embryonic FAD mice. Mitochondrial distribution, fission and fusion were examined using electron microscopy and western blot analysis in the brain tissue of AD mice at different ages. Metabolomic profiling in brain and plasma of FAD mice was done using gas-chromatograph/mass-spectrometry and HPLC analysis. Assessment of mitochondrial motility, distribution, dynamics, morphology, and metabolomic profiling revealed the specific effect of each FAD mutation on the development of mitochondrial stress and dysfunction. Inhibition of mitochondrial trafficking was characteristic for embryonic neurons from mice expressing mutant human presenilin 1, PS1(M146L) and the double mutation of human amyloid precursor protein APP(Tg2576) and PS1(M146L) contributing to the increased susceptibility of neurons to excitotoxic cell death. Significant changes in mitochondrial morphology were detected in APP and APP/PS1 mice. All three FAD models have shown a loss of the integrity of synaptic mitochondria and energy production. Metabolomic profiling revealed mutation-specific changes in the levels of metabolites reflecting altered energy metabolism and mitochondrial dysfunction in brain of FAD mice. Metabolic biomarkers adequately reflected gender differences similar to that reported for AD patients and correlated well with the biomarkers currently used for diagnosis in humans.