NADH fluorescence lifetime imaging microscopy reveals selective mitochondrial dysfunction in neurons overexpressing alzheimer’s disease–related proteins
Niederschweiberer, Moritz A.
Schaefer, Patrick M.
Singh, Larry N.
Frontiers in Molecular Biosciences ; 8 (2021). - Art.-Nr. 671274. - eISSN 2296-889X
Link to original publicationhttps://dx.doi.org/10.3389/fmolb.2021.671274
InstitutionsUKU. Klinik für Neurologie
Institut für Medizinische Systembiologie
Zentrum für Translationale Bildgebung (MoMAN)
UKU. Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung
External cooperationsCharité – Universitätsmedizin Berlin
University of Pennsylvania
University of the Sciences
Alzheimer’s disease (AD), the most prevalent form of dementia, affects globally more than 30 million people suffering from cognitive deficits and neuropsychiatric symptoms. Substantial evidence for the involvement of mitochondrial dysfunction in the development and/or progression of AD has been shown in addition to the pathological hallmarks amyloid beta (Aβ) and tau. Still, the selective vulnerability and associated selective mitochondrial dysfunction cannot even be resolved to date. We aimed at optically quantifying mitochondrial function on a single-cell level in primary hippocampal neuron models of AD, unraveling differential involvement of cell and mitochondrial populations in amyloid precursor protein (APP)-associated mitochondrial dysfunction. NADH lifetime imaging is a highly sensitive marker-free method with high spatial resolution. However, deciphering cellular bioenergetics of complex cells like primary neurons has still not succeeded yet. To achieve this, we combined highly sensitive NADH lifetime imaging with respiratory inhibitor treatment, allowing characterization of mitochondrial function down to even the subcellular level in primary neurons. Measuring NADH lifetime of the same neuron before and after respiratory treatment reveals the metabolic delta, which can be taken as a surrogate for cellular redox capacity. Correlating NADH lifetime delta with overexpression strength of Aβ-related proteins on the single-cell level, we could verify the important role of intracellular Aβ-mediated mitochondrial toxicity. Subcellularly, we could demonstrate a higher respiration in neuronal somata in general than dendrites, but a similar impairment of somatic and dendritic mitochondria in our AD models. This illustrates the power of NADH lifetime imaging in revealing mitochondrial function on a single and even subcellular level and its potential to shed light into bioenergetic alterations in neuropsychiatric diseases and beyond.
Joint Industrial Research Program / BMWi [18239N]
DFG [SCHA 2182/1-1]
DFG [SCHA 2182/1-1]
Is supplemented byhttps://www.frontiersin.org/articles/10.3389/fmolb.2021.671274/full#supplementary-material
Subject headings[GND]: Mitochondrium | Energiestoffwechsel | Alzheimerkrankheit | NADH | Amyloid (beta)
[LCSH]: Mitochondria | Energy metabolism | Alzheimer’s disease | NAD (Coenzyme) | Amyloid beta-protein
[Free subject headings]: Redox imaging
[DDC subject group]: DDC 570 / Life sciences | DDC 610 / Medicine & health
LicenseCC BY 4.0 International
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DOI & citation
Please use this identifier to cite or link to this item: http://dx.doi.org/10.18725/OPARU-38172