Wojciech Michno (Presenter)
Sahlgrenka Academy at University of Gothenburg
Bio: Wojciech Michno has studied in Poland, Sweden, Norway, and the United States. He is a United World College (Norway) scholar and a Macalester College (USA) alumnus. At the university he completed two degrees in parallel, one in Chemistry and one in Neuroscience, with a focus on molecular neurobiology. Wojciech did his master’s thesis in pharmacology, and is now completing his PhD in analytical neurochemistry working with Alzheimer’s disease at Sahlgrenska Academy, University of Gothenburg, Sweden.
Authorship: Wojciech Michno (1,2), Ibrahim Kaya (1,2), Stina Syvänen (3), and Jörg Hanrieder (1,2,4)
(1) Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden (2) Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal Sweden (3) Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden (4) Department of Molecular Neuroscience, Institute of Neurology, University College London, UK
| Short Abstract Alzheimer's disease (AD) is a neurodegenerative disease, of which the underlying pathological mechanism is still not understood. The disease is characterized by accumulation of Amyloid-β peptides into different extracellular plaques. Plaques have also been found in non-demented pathological aging patients. Therefore, discrimination between structural and molecular plaque architecture are of interest to resolve plaque pathology in AD. MALDI IMS was utilized to elucidated lipid environment in AD tissue. Then, a hyperspectral imaging paradigm employing Amyloid-β aggregate binding LCOs and an in-house software was used to differentiate between different types of plaques. Clear localization of several sphingolipids in plaques and their surroundings, as well as lipid composition differences between the different plaques, were identified through a true multimodal imaging paradigm. |
Long Abstract
Alzheimer's disease is a chronic, neurodegenerative disease that affects more than 44 million people worldwide and accounts for about 60% of all dementia cases (1,2). It is characterized by cognitive decline and memory loss as a result of neuronal degeneration and loss of synapses (3). The exact mechanisms underlying AD pathogenesis are still not fully understood, which significantly hampers the development of therapeutic treatment strategies. These have however been linked to progressive accumulation of hyperphosphorylated tau protein into intraneuronal tangles and Amyloid-β peptides into intra- and extracellular deposits or plaques (2).
While this amyloid pathology has been suggested to be a critical inducer of AD pathogenesis, the correlation of plaque burden and AD progression has been questioned. For instance, amyloid plaques have been found in pathological ageing (PA) patients that were cognitively normal (4). However, Amyloid-β plaques present in PA brains are mostly diffuse in nature, while plaques in AD brain tissue are mostly mature/compact. Diffuse plaques can be a consequence of an alternative, neuroprotective aggregation mechanism. Alternatively, diffuse plaques can represent an immature non-toxic state of mature compact amyloid plaques. The factors that promote neurotoxic plaque formation are still unknown.
Changes in amyloid peptide truncation and plaque associated neuronal lipid species have been implicated in the proteopathic mechanisms in AD (5,6). Several studies have suggested gangliosides binding to the Amyloid-β peptides serve as a seed for fibrillogenesis (7), similarly hypercholesterolemia has also been associated with the acceleration of the AD pathology (8). Until today, no clear association between different lipid species and Amyloid-β in plaques, particularly of distinct structures, has been elucidated. Therefore, a chemical imaging that allows the efficient discrimination of structural and molecular plaque architecture is of essential interest to resolve Amyloid-β plaque pathology in AD. The majority of current biochemical methods lack the necessary molecular specificity to study plaque chemistry, highlighting the need to develop and employ new bioanalytical techniques, such as mass spectrometry.
MALDI imaging mass spectrometry is an advanced technique to reveal the spatial distribution maps of lipids, peptides and proteins in neuroscience (9). When used in combination with conventional immunohistochemical/histochemical staining, it allows for superior insight into a variety of morphological aspects in tissue samples. Taking into consideration the need to distinguish plaques based on their morphology and structures, histological stains that allow for differentiation between different components and types of plaques are of great importance. In particular, Luminescent conjugated oligothiophenes (LCOs) have been suggested to exhibit differential binding to the various amyloid aggregation states (10). In particular, q-FTAA (quattro-formylthiophene, green) has been suggested to respond only to mature Aβ amyloid fibrils, whereas h-FTAA (hepta-FTAA, red) binds to mature amyloid fibrils and early pre-fibrillar states (diffuse plaques).
The aim of this study was to employ MALDI imaging mass spectrometry (IMS) in combination with chemical and immuno-labeling strategies for multimodal and hyperspectral imaging of individual Amyloid-β plaques in transgenic AD mice (tgSwe) and human tissue. The use of sublimation as a method for matrix application provided us with high resolution (down to 10μm) images of individual lipid species, without perturbation of the underlying fibrillary structures in the Amyloid-β plaques. Thereafter, Luminescent conjugated oligothiophenes (LCO), in combination with fluorescence immunolabeling, were used to detect and discriminate Amyloid-β plaque heterogeneity based on their chemical and structural features. Finally, hyperspectral imaging in combination with an in-house developed software, was used for characterization of Amyloid-β aggregates based on multiplexed image acquisition with two wavelength excitation and linear unmixing of the two fluorophores.
Our results indicate localization of several sphingolipids to the plaques and their surroundings. Further, differences in lipid composition between the different Amyloid-β plaques were identified.
References & Acknowledgements:
(1) Alzheimer’s Disease International. Alzheimers Disease International. World Alzheimer Report 2014. (2014).
(2) Blennow, K., de Leon, M. J. & Zetterberg, H. Alzheimer’s disease. Lancet 368, 387–403 (2006).
(3) Burns, A. & Iliffe, S. Alzheimer’s disease. BMJ 338, b158 (2009).
(4) Moore, B. D. et al. Overlapping profiles of Abeta peptides in the Alzheimer’s disease and pathological aging brains. Alzheimers. Res. Ther. 4, 18 (2012).
(5) Di Paolo G. and Kim TW, Nat Rev Neurosci, 2011, 12(5): p.284-296
(6) Selkoe, D.J. and Schenk D., Annu Rev Pharmacol Toxicol, 2003.43: p. 545-84
(7) Yamamoto, N. et al. Ganglioside-induced Toxic Soluble Aβ Assembly ITS ENHANCED FORMATION FROM AβBEARING THE ARCTIC MUTATION. Journal of Biological Chemistry, 2007, 282 (4), 2646-2655.
(8) Refolo, L. et al. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiology of disease 2000, 7 (4), 321-331.
(9) Hanrieder, J. r.; Phan, N. T.; Kurczy, M. E.; Ewing, A. G., Imaging mass spectrometry in neuroscience. ACS chemical neuroscience 2013, 4 (5), 666-679.
(10) K. P. Nilsson, A. Aslund, I. Berg, et al., ACS Chem Biol
2007, 2. 553-60
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