Hypothesis and Theory: Characterizing Abnormalities of Energy Metabolism Using a Cellular Platform as a Personalized Medicine Approach for Alzheimer’s Disease

Abstract

Sporadic or late-onset Alzheimer’s disease (LOAD) is characterized by slowly progressive deterioration and death of CNS neurons. There are currently no substantially disease-modifying therapies. LOAD pathology is closely related to changes with age and include, among others, accumulation of toxic molecules and altered metabolic, microvascular, biochemical and inflammatory processes. In addition, there is growing evidence that cellular energy deficits play a critical role in aging and LOAD pathophysiology. However, the exact mechanisms and causal relationships are largely unknown. In our studies we tested the hypothesis that altered bioenergetic and metabolic cell functions are key elements in LOAD, using a cellular platform consisting of skin fibroblasts derived from LOAD patients and AD-unaffected control individuals and therefrom generated induced pluripotent stem cells that are differentiated to brain-like cells to study LOAD pathogenic processes in context of age, disease, genetic background, cell development, and cell type. This model has revealed that LOAD cells exhibit a multitude of bioenergetic and metabolic alterations, providing evidence for an innate inefficient cellular energy management in LOAD as a prerequisite for the development of neurodegenerative disease with age. We propose that this cellular platform could ultimately be used as a conceptual basis for a personalized medicine tool to predict altered aging and risk for development of dementia, and to test or implement customized therapeutic or disease-preventive intervention strategies.

Ganoderic Acid A To Alleviate Neuroinflammation of Alzheimer’s Disease in Mice by Regulating the Imbalance of the Th17/Tregs Axis

“…The pentose phosphate pathway provided NAPDH to fatty acid βoxidation, which then produced acetyl-CoA into the TCA cycle as the energy supply. 47 In the current study, enhanced fatty acid metabolism was shown in the D-gal group, which is consistent with published reports. As reported, the Treg transcription factor Foxp3 could reprogram T cell metabolism by suppressing glycolysis and enhancing oxidative phosphorylation.…”

“…The increased lactate level in the d -gal + GAA group implied that the energy supply of neurons had been restored by means of lactolysis. The pentose phosphate pathway provided NAPDH to fatty acid β-oxidation, which then produced acetyl-CoA into the TCA cycle as the energy supply . In the current study, enhanced fatty acid metabolism was shown in the d -gal group, which is consistent with published reports.…”

Nicotinamide riboside and caffeine partially restore diminished NAD availability but not altered energy metabolism in Alzheimer's disease

“…We previously observed reductions of NAD + and NADH along with other bioenergetic alterations in cells from LOAD patients, including skin fibroblasts and iPSC‐derived NPCs and astrocytes (Ryu, Bormann, et al, 2021; Ryu, Cohen, et al, 2021; Sonntag et al, 2017). Here, we hypothesized that treatment with NR and caffeine might restore NAD levels, and “correct” the bioenergetic profiles of LOAD cells.…”

“…PPP leads to reduction of NAPD + to NAPDH, used for fatty acid biosynthesis and regeneration of reduced glutathione. Many brain disorders, including LOAD, show evidence of abnormal bioenergetics, which may lead to diminished neuroprotective capacities, enhancing and accelerating age‐related neuronal decline (Jove et al, 2014; Mattson & Arumugam, 2018; Ryu, Bormann, et al, 2021; Ryu, Cohen, et al, 2021; Sun et al, 2016; Swerdlow & Khan, 2004).…”

“…NAD concentration is determined by new synthesis and recycling (Figure 1a and reviewed in [Canto et al, 2015; Covarrubias et al, 2021; Verdin, 2015]). NAD levels, and factors required for its synthesis and/or recycling, such as nicotinamide mononucleotide adenylyl transferases (NMNAT), diminish with age and in neurodegenerative diseases, including LOAD (Ali et al, 2016; Covarrubias et al, 2021; Lautrup et al, 2019; Ryu, Bormann, et al, 2021; Ryu, Cohen, et al, 2021; Sonntag et al, 2017; Verdin, 2015; Zhu et al, 2015) Because reduced NAD + recycling impairs glycolysis and OxPhos and enhanced NAD + metabolism can protect neurons from degeneration, NAD has been suggested as a therapeutic agent in neurodegenerative diseases (Braidy & Liu, 2020b; Covarrubias et al, 2021; Lautrup et al, 2019; Liu et al, 2008; Verdin, 2015).…”