Jörg Hanrieder (Presenter)
University of Gothenburg
Bio: I graduated with a MSc in chemistry from Leipzig University in 2005. During my undergraduate program, I got the chance to perform parts of my master studies in medicinal and analytical chemistry at Ohio University with a stipend from the German academic exchange service (DAAD). After spending some month as research associate at Adelaide University, Australia, I enrolled as PhD student in analytical chemistry at Uppsala University under the supervision of Prof Jonas Bergquist. During my PhD, I worked on neuropeptide and protein profiling in neurodegenerative diseases using MALDI imaging mass spectrometry as well as standard proteomic setups. After graduating in 2011, I joined the group of Prof Andrew Ewing at Chalmers University, Gothenburg, Sweden on a Postdoc grant funded by the swedish research council. Over the course of my education and postdoc, I managed to publish 43 peer reviewe
Authorship: Jörg Hanrieder
(1) University of Gothenburg, Sweden, (2) University College London, UK
| Short Abstract The major pathological hallmarks of Alzheimer's disease (AD) is the progressive accumulation and aggregation of beta-amyloid (A) and hyperphosphorylated-tau, into neurotoxic deposits. A aggregation has been suggested as a possibly critical, early inducer driving the disease progression. However, the exact mechanisms underlying A pathology remain unknown, which hampers the development of effective AD treatment strategies. We here, developed a multimodal chemical imaging paradigm employing hyper spectral fluorescent amyloid imaging together with MALDI imaging mass spectrometry to probe Abeta plaque pathology in transgenic AD mice. The results show distinct localisation of e.g. ceramides to compact deposits, while phospho-ceramides localise to diffuse aggregates. The results highlight the potential of IMS for discovering novel pathological mechanisms underlying neurodegeneration. |
Long Abstract
Introduction
Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting 12% over 65 (1). The exact mechanisms underlying AD pathogenesis are still not fully understood, significantly hampering the development of therapeutic treatment strategies. In AD, cognitive decline has been linked to formation of β-amyloid (Abeta) deposits as senile plaques as well as intracellular neurofibrillary tangles comprised of hyper-phosphorylated tau protein (2). The neuropathology in genetic- and sporadic AD is similar with respect to protein accumulation. Changes in peptide truncation and plaque associated neuronal lipid species have been implicated with proteopathic mechanisms in AD (4). Moreover , plaque pathology represents itself in a heterogeneous variety of senile deposits including diffuse and mature, cored plaques. Interestingly, patients that display high amyloid load in the brain without cognitive deficits were found to show only diffuse plaques. It is therefore of particular interest to characterize the chemical phenotype (peptide truncation, associated lipids) of diffuse plaques that aggregate into mature plaques and to elucidate how these plaque characteristics correlate with spread of AD pathology and cognitive decline.
Methods
Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides and proteins in biological tissues. We have previously demonstrated the potential of IMS for probing plaque chemistry in transgenic AD mice (5-7). We here developed a novel chemical imaging paradigm using IMS and fluorescent amyloid staining. For that we employed luminescent oligothiophene (LCO) amyloid probes that bind amyloid structures differentially based on the fibrillation degree. Moreover, these probes exhibit distinct excitation and emission profiles allowing for multiplexed staining and hyper spectral optical imaging. This hyperspectral/multimodal chemical imaging approach was used to probe lipid chemistry associated with structural plaque heterogeneity in transgenic AD mice.
Results
Multivariate image analysis revealed an inverse localization of ceramides and their matching metabolites to diffuse and cored structures within single plaques. Moreover, lysophospholipids implicated in neuroinflammation along with eicosanoide - precursor fatty acid containing phospholipids were increased in Abeta deposits. Finally, several lipids, including phosphatidylinositols,that are effective ligands of the TREM2 receptor which in turn has been implicated in AD pathology were found to localize to the diffuse prefibrillar Abeta structures..
Conclusions & Discussion
Taken together, results presented here highlight the potential of high resolution MALDI-IMS when combined with complementary methods, such as structural differentiation based on LCO, to offer an opportunity to elucidate chemical differences in plaque populations. Here, this approach was utilized to reveal clear involvement of phospholipids and ceramide metabolites in formation of morphologically heterogeneous plaque morphology. Such morphological difference in plaque pathology as outlined by differential lipid distribution, emphasize the need for chemical analysis of the Aβ in order to shine further light on plaque formation and maturation.
The results further verify previous findings on lipid pathology in AD obtained from clinical studies on CSF as well as shed new light on AD associated sphingolipid processing mechanisms. In summary, these data highlight the potential of multimodal hyperspectral imaging as a powerful technology to probe neuropathological mechanisms in situ.
References & Acknowledgements:
(1) Selkoe, D.J. and Schenk D., Annu Rev Pharmacol Toxicol, 2003.43: p. 545-84
(2) Thal D.R. et al., Neurology, 2002. 58(12): p. 1791-800
(3) Lord, A., et al., Neurobiol Aging, 2006. 27(1): p. 67-77
(4) Di Paolo G. and Kim TW, Nat Rev Neurosci, 2011, 12(5): p.284-296
(5) Carlred et al. J Neurochemistry 2016, 183 (3):469-478
(6) Kaya et al. ACS Chem Neurosci 2017,8(2):347-355
(7) Kaya et al. Anal Chem 2017, 89(8):4685-4694
| Description | Y/N | Source |
| Grants | no | |
| Salary | no | |
| Board Member | no | |
| Stock | no | |
| Expenses | no |
IP Royalty: no
| Planning to mention or discuss specific products or technology of the company(ies) listed above: | no |