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Systems Biology of Bioenergetic Shifts in Alzheimer’s Disease and Aging


Aging increases the risk of neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s Disease. AD is a progressive neurodegeneration with loss of cognitive memory, leading to dementia. The goal of this work is to systematically trace an upstream metabolic or energetic shift in aging and AD to identify targets to delay or even reverse the course of aging and pathologies in AD. Based on the epigenetic oxidative redox shift (EORS) theory of aging, we developed the hypothesis that age- and AD-related oxidative shifts deplete NADH levels in hippocampal neurons, which further trigger the downstream energetic and metabolic shifts sensed at NAD+/NADH redox sensitive sites. Regulated by redox-sensitive transcription factors, metabolic shifts are enforced epigenetically, which initiate a vicious cycle and exacerbate the course of aging and AD.

This work investigates upstream oxidative shifts in NADH redox states and verifies causative links to systematic downstream metabolic and energetic networks. As nicotinamide adenine dinucleotide (NAD and NADH) plays critical roles in metabolic oxidation-reduction reactions in energetic pathways as well as redox detoxification systems, we further examined if these age-related oxidized free NADH redox states and depletion of NADH are reversible and restored with external redox modification in primary cultures by manipulating different redox potentials of Cysteine/Cystine (Cys/CySS). NADH measurements were performed on live neurons of primary hippocampal cultures of non-transgenic (NTg) and triple-transgenic AD mouse model (3xTg-AD) across the age-span, by using the fluorescence lifetime imaging microscopy (FLIM) technique. This FLIM technique is a non-invasive approach of the intrinsic fluorescence in NADH. After transformation of pixels of FLIM images by Fast Fourier Transform (FFT), we were able to distinguish different NADH lifetimes, analyze and quantify free and enzyme-bound NADH in subcellular compartments in the phasor plot. We found a strong age effect that diminished the free NADH levels in mitochondria, cytoplasm and nuclei with further depletion with AD genetic load. With an imposed oxidized Cys/CySS state of 0 mV in neuron culture, we found a lower capacity for maintaining free NADH in old age versus young age neurons of both NTg and 3xTg-AD mouse neurons. Remarkably, under an external imposed Cys/CySS reductive state, the mitochondrial free NADH levels were rejuvenated to the levels of young age neurons in both NTg and 3xTg-AD mouse neurons. Our findings suggest a potential reductive treatment to reverse the loss of free NADH in old and AD neurons.

To test our hypothesis of an age-related metabolic shift triggered by oxidation in NADH redox states, we applied untargeted Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS) to globally detect and measure the metabolite levels from NTg and 3xTg-AD mouse hippocampal brains across the age-span. We observed strong age-related global elevations up to 2-3-fold in energy metabolism including glycolytic ATP-produced steps, fatty acid b-oxidation and branched chain amino acid metabolism. The direction of metabolic changes with age pivoted at NAD+/NADH redox sensitive dehydrogenases. We found for the first-time age-related decreases in the upstream metabolites of dehydrogenases and increases in the downstream metabolites of glycolysis and the TCA cycle. Our results support the hypothesis and provide a potential reductive treatment to possibly counter AD and extend healthy lifespan, by reversal of low free NADH levels in old and Alzheimer’s neurons via a series of NADH-sensor mechanisms.

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