Defects in Mitochondrial Dynamics and Metabolomic Signatures of Evolving Energetic Stress in Mouse Models of Familial Alzheimer's Disease

Abstract

BackgroundThe 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 AD pathophysiology, however, no comprehensive study exists that evaluates the effect of different familial AD (FAD) mutations on mitochondrial function, dynamics, and brain energetics.Methods and FindingsWe characterized early mitochondrial dysfunction and metabolomic signatures of energetic stress in three commonly used transgenic mouse models of FAD. 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 demonstrated 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 brains 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.ConclusionsMutation-specific alterations in mitochondrial dynamics, morphology and function in FAD mice occurred prior to the onset of memory and neurological phenotype and before the formation of amyloid deposits. Metabolomic signatures of mitochondrial stress and altered energy metabolism indicated alterations in nucleotide, Krebs cycle, energy transfer, carbohydrate, neurotransmitter, and amino acid metabolic pathways. Mitochondrial dysfunction, therefore, is an underlying event in AD progression, and FAD mouse models provide valuable tools to study early molecular mechanisms implicated in AD.

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

“…Previous studies using in vivo proton magnetic resonance spectroscopy ( 1 H MRS) found decreases in N-acetylasparatate and glutamate, and an increase in myo-inositol concentrations in APP/PS1 mice (Chen et al, 2012;Marjanska et al, 2005). Glycolytic pathways involving the Kreb's cycle, and neurotransmitter and amino acid metabolism, were found to be significantly affected in APP/PS1 mouse brain (Trushina et al, 2012). Furthermore, 1 H NMR metabolomics studies found altered ascorbate, creatine, γ-aminobutyric acid and NAA in APP/PS1 mouse brain, and altered acetate, citrate, glutamine and methionine in blood plasma (Graham et al, 2013b).…”

“…It holds considerable potential as a discovery platform for identifying novel diagnostic biomarkers for AD but also many other neurodegenerative diseases. Metabolomics studies have previously been undertaken in APP/PS1 mice (Chen et al, 2012;GonzalezDominguez et al, 2015a;González-Domínguez et al, 2014;Graham et al, 2013b;Marjanska et al, 2005;Trushina et al, 2012;Yao et al, 2009), however, the majority of these studies (including our own (Graham et al, 2013b)) suffer from limitations commonly befalling many metabolomics investigations conducted to date. The current study was designed having noted earlier approaches to undertake a more robust metabolomics evaluation of this important model of AD.…”

Metabolomics in the Study of Alzheimer's Disease

“…Mitochondrial dysfunction has been suggested to underlie AD pathophysiology [111]. Deposition of heavy metals and alteration of the mitochondrial functionality are some of the facts and effects of oxidative stress observed in AD process [112].…”

“…Trushina et al studied the mitochondrial dynamics and function (motility, distribution, ultrastructure, etc) in neurons and brain tissue of three transgenic mice models expressing mutant human APP (Tg2576), PS1 (M146L mice) and the double mutation APP/PS1 [111].…”

“…GC-MS combined with multivariate statistical analysis by means of PLS-DA showed different gender related metabolic profiles leading to the comparison exclusively of females of all types of mice (three transgenic and one control mice). As a result, significant alterations in the levels of metabolites involved in energy metabolism including nucleotide metabolism, mitochondrial Krebs cycle, energy transfer, carbohydrate, neurotransmitter and amino acid metabolic pathways, were observed to be linked to familial AD [111] (Fig. 6).…”