Metabolic imaging in Alzheimer´s Disease using NADH autofluorescence
Schaefer, Patrick Michael
RefereeArnim, Christine A.F. von
FacultiesFakultät für Naturwissenschaften
InstitutionsKlinik für Neurogeriatrie und neurologische Rehabilitation RKU - Universitäts- und Rehabilitationskliniken Ulm
LicenseCC BY 4.0 International
Mitochondrial alterations are a major hallmark of all neurodegenerative diseases and are thought to be one underlying cause of neuronal death in Alzheimer´s disease. Amyloid β as well as the amyloid precursor protein are said to have a toxic effect on the electron transport system, thereby impairing mitochondrial respiration especially in neurons of the hippocampus. This high selective vulnerability of different cells and mitochondrial populations to toxic stimuli in neurodegeneration is still not understood at all. The aim of my thesis was to clarify the role of the subcellular localization of Aβ and APP on the selective vulnerability of mitochondria and to develop a novel approach to visualize mitochondrial respiration microscopically. I could demonstrate that reduced mitochondrial respiration is mainly conferred by intracellular, most likely intramitochondrial Aβ. This direct effect underlines the rational for a selective vulnerability of mitochondrial populations due to cell-specific transport differences of APP and Aβ. Consequently, I established an imaging approach based on NADH autofluorescence to visualize mitochondrial respiration on the subcellular level. By thorough correlations of NADH autofluorescence lifetime to high-resolution respirometry I could determine confounding factors, first and formost the pH. Parallel imaging of NADH and pH allowed a revolution in using NADH autofluorescence for quantifying even subtle changes in mitochondrial respiration on the subcellular level. To sum up, I could identify a potential underlying cause of the selective mitochondrial vulnerability in Alzheimer´s disease by highlighting the importance of Aβ localization in conferring mitochondrial toxicity. In addition, I provide a novel, functional imaging approach to shed light onto metabolic alterations of specific mitochondrial pools, cell types or brain regions. This will allow to clarify mitochondrial dysfunction not only in Alzheimer´s disease but it will provide a ubiquitous tool for multiple metabolic diseases.
This research was funded by the German Federal Ministry of Economics and Energy (BMWi) within the Promotion of Joint Industrial Research Program (IGF) due to a decision of the German Bundestag. It was part of the research project 18239 N by the Association for Research in Precision Mechanics, Optics and Medical Technology (F.O.M.) under the auspices of the German Federation of Industrial Research Associations (AiF).
Subject HeadingsNADH [GND]
Energy metabolism [MeSH]
Alzheimer disease [MeSH]