Systems biology identifies preserved integrity but impaired metabolism of mitochondria due to a glycolytic defect in Alzheimer's disease neurons

Aging Cell
Pierre TheureyJochen H M Prehn

Abstract

Mitochondrial dysfunction is implicated in most neurodegenerative diseases, including Alzheimer's disease (AD). We here combined experimental and computational approaches to investigate mitochondrial health and bioenergetic function in neurons from a double transgenic animal model of AD (PS2APP/B6.152H). Experiments in primary cortical neurons demonstrated that AD neurons had reduced mitochondrial respiratory capacity. Interestingly, the computational model predicted that this mitochondrial bioenergetic phenotype could not be explained by any defect in the mitochondrial respiratory chain (RC), but could be closely resembled by a simulated impairment in the mitochondrial NADH flux. Further computational analysis predicted that such an impairment would reduce levels of mitochondrial NADH, both in the resting state and following pharmacological manipulation of the RC. To validate these predictions, we utilized fluorescence lifetime imaging microscopy (FLIM) and autofluorescence imaging and confirmed that transgenic AD neurons had reduced mitochondrial NAD(P)H levels at rest, and impaired power of mitochondrial NAD(P)H production. Of note, FLIM measurements also highlighted reduced cytosolic NAD(P)H in these cells, and extracellula...Continue Reading

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Citations

Jan 30, 2020·International Journal of Molecular Sciences·Luisa GallaElisa Greotti
Apr 3, 2020·Journal of Cellular Physiology·Bor Luen Tang
Sep 24, 2020·International Journal of Molecular Sciences·Carmen Martínez-Cué, Noemí Rueda
Aug 7, 2019·Aging·Niamh M C ConnollyPaola Pizzo
Jul 19, 2019·Oxidative Medicine and Cellular Longevity·Giulia Rigotto, Emy Basso
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Oct 13, 2020·Journal of Alzheimer's Disease : JAD·Zhenting HuangZhiyou Cai
Dec 15, 2020·Cell Calcium·Riccardo Filadi, Elisa Greotti
Apr 4, 2021·International Journal of Molecular Sciences·Mehdi EshraghiSaeid Ghavami
May 18, 2021·Frontiers in Neuroscience·Xin ZhangLiqin Zhao
Nov 11, 2021·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Emrin HorgusluogluUNKNOWN Alzheimer Disease Metabolomics Consortium

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Methods Mentioned

BETA
transgenic
glycosylation
Protein Assay

Software Mentioned

MATLAB
Fiji
Seahorse XF Analyzer
Sims
WTsim
FLIM

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