TY - JOUR A1 - Niederschweiberer, Moritz A1 - Schaefer, Patrick M. A1 - Singh, Larry N. A1 - Lausser, Ludwig A1 - Bhosale, Devyani A1 - Hesse, Raphael A1 - Calzia, Enrico A1 - Kestler, Hans A. A1 - Rueck, Angelika A1 - Wallace, Douglas A1 - Einem, Bjoern von A1 - Arnim, Christine A. F. von T1 - NADH Fluorescence Lifetime Imaging Microscopy Reveals Selective Mitochondrial Dysfunction in Neurons Overexpressing Alzheimer’s Disease–Related Proteins JF - Frontiers in Molecular Biosciences N2 - 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. UR - https://doi.org/10.3389/fmolb.2021.671274 KW - mitochondria KW - energy metabolism KW - Alzheimer’s disease KW - NADH KW - redox imaging KW - amyloid beta Y1 - 2021 UR - https://doi.org/10.3389/fmolb.2021.671274 UR - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:573-27224 SN - 2296-889X N1 - Section: Molecular Diagnostics and Therapeutics VL - 8 PB - Frontiers CY - Lausanne ER - TY - JOUR A1 - Hesse, Raphael A1 - Einem, Bjoern von A1 - Wagner, Franziska A1 - Bott, Patricia A1 - Schwanzar, Daniel A1 - Jackson, Rosemary A1 - Föhr, Karl Josef A1 - Lausser, Ludwig A1 - Kroker, Katja S. A1 - Proepper, Christian A1 - Walther, Paul A1 - Kestler, Hans A. A1 - Spires-Jones, Tara A1 - Boeckers, Tobias A1 - Rosenbrock, Holger A1 - Arnim, Christine A. F. von T1 - sAPPβ and sAPPα increase structural complexity and E/I input ratio in primary hippocampal neurons and alter Ca2+ homeostasis and CREB1-signaling JF - Experimental Neurology UR - https://doi.org/10.1016/j.expneurol.2018.02.010 KW - sAPP KW - AD KW - neuronal plasticity KW - neurodevelopment KW - CREB-1 signaling Y1 - 2018 UR - https://doi.org/10.1016/j.expneurol.2018.02.010 SN - 0014-4886 VL - (2018) IS - 304 SP - 1 EP - 13 PB - Elsevier CY - Amsterdam ER -