Jörg Hanrieder

Research interest

The research in our lab comprises both the development of innovative spatial biology techniques including imaging mass spectrometry, functional light microscopy and spatial transcriptomics and proteomics. Our central aim is to elucidate molecular aspects of brain amyloidosis associated with neurodegenerative processes particularly in Alzheimer’s disease (AD). In detail, we focuses on delineating beta-amyloid (Aβ) peptide and Tau protein aggregation dynamics, as well as the associated spatial lipid-, gene- and protein signatures in AD and other dementias with the aim to understand the mechanism behind transforming proteins like beta-amyloid (Aβ) and tau from being a non-toxic monomer to a neurotoxic oligomeric species that ultimately leads to nerve cell death and cognitive decline.

Here, our group has over the last years been working on different molecular imaging modalities to probe chemical and structural aspects of amyloid pathology in AD (1-4). We developed a novel imaging paradigm that combined structure specific luminescent amyloid dyes with fluorescent imaging in combination with mass spectrometry imaging (MSI). Using this strategy, we were able to delineate the chemical traits, peptides and lipids, associated with plaque polymorphism in genetic AD mouse models and human brain (4,5). We used this approach to map chemical signatures of heterogenous amyloid pathology across the AD continuum. We developed a deep learning model based on the hyperspectral data to identify plaque subtypes across different patients and forms of AD (7,8).

Group members

The imaging experiments developed by our group allow to characterize chemical and structural features of AD pathology beyond what is discernible using established microscopy techniques. However, protein aggregation and deposition, is a highly dynamic process. This requires experimental setups that allow to monitor these processes as a function of time as the fibrillization dynamics of Aβ are of integral relevance in AD pathogenesis. To address this issue, our group is currently working on expanding imaging mass spectrometry towards stable isotope labelling to measure protein aggregation kinetics (iSILK), which we use to quantify amyloid peptide aggregation dynamics in genetic mouse models of AD. We have recently completed and published a first iSILK study where we follow plaque formation in APP knock-in mice (9).

These iSILK experiments allowed for the first time to visualize aggregation dynamics of different Aβ peptides within single plaques and across different brain regions in evolving plaque pathology from early deposition to later plaque growth. The results show that plaques in APP NLGF/NLGF mice form via early deposition of Aβ1-42 into compact core which is followed by plaque growth by homogenous deposition throughout the plaque. Later events in early plaque pathology involve deposition in the hippocampus, and secretion and deposition of Ab1-38 (9).

Most recently we expanded our research towards using iSILK MS imaging to guide spatial transcriptomics (10) to understand how plaque maturation in ageing models of amyloid pathology (APP NLF/NLF ) affects cellular gene expression in proximal- and distal cells. Interestingly, in both 10 and 18mo mice we observed that synaptic genes correlated negatively with plaque age. This is interesting as amyloid has long been suspected to affect synaptic genes and proteins, though these processes are convoluted in whole tissue transcriptomics (11).

• 1, Michno W, Kaya I, Nyström S, Guerard L, Nilsson KPR, Hammarström P, Blennow K, Zetterberg H, Hanrieder J.*“Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals Aβ Aggregation Dependent Anionic Lipid Accumulations and Metabolism” 2018 Anal Chem. 90(13):8130-8138. PMID: 29856605
• 2, Dreos A., Ge J., Najera F., Ergette Tebikachew B., Perez-Inestrosa E., Zetterberg H., Blennow, K., Moth-Poulsen, K., Hanrieder J.* ” Investigating New Applications of a Photoswitchable Fluorescent Norbornadiene as a Multifunctional Probe for Delineation of Amyloid Plaque Polymorphism” 2023 ACS Sensors 8(4):1500-1509 PMID: 36946692
• 3, Ge J., Koutarapu S., Jha D., Dulewicz M., Zetterberg H., Blennow K., Hanrieder J.* ”Tetramodal Chemical Imaging Delineates the Lipid-Amyloid Peptide Interplay at Single Plaques in Transgenic Alzheimer’s Disease Models” 2023 Anal. Chem. 95(10):4692-4702 PMID: 36856542
• 4, Wehrli P., Michno W, Guerard L, Fernandes-Rodriguez J, Zetterberg H, Bergh A, Blennow K, Hanrieder J.*“Spatial Chemometrics and Comprehensive Chemical Imaging based Molecular Histopathology Delineates Anatomical Heterogeneity at Single Pixel Resolution” 2023 J Amer Chem Soc Au 3(3):762-774
• 5, Michno W, Nyström S, Lashley T., Wehrli P., Brinkmalm G., Kaya I, Brinet, D., Guerard L, Syvänen S., Sehlin D., Nilsson KPR, Hammarström P, Blennow K, Zetterberg H, Hanrieder J.* “Pyroglutamation of Aβx-42 followed by Aβ1-40 deposition underlie priming and maturation of diffuse into cored plaque morphotypes in progressing Alzheimer’s disease pathology” 2019 J Biol Chem 294(17):6719-6732. PMC6497931
• 6, Pagnon de la Vega M., Giedraitis V., Michno W. Kilander L, Guener G, Zielinski M, Brundin RM, Danfors T, Söderberg L, Alafuzoff I, Nilsson LNG, Erlandsson A, Willbold D, Schröder GF, Müller SA, Hanrieder J,  Lichtenthaler SF, Lannfelt L, Sehlin D and Ingelsson M. “The Uppsala APP mutation causes early onset Alzheimer’s  by altering APP processing and increasing amyloid-β fibril formation” Science Transl Med 2021 13(606):eabc6184. PMID:34380771
• 7, Michno W., Kotarapu S., Ge J., Tommey C., Jha, D. Stringer K., Minta K., Zetterberg H., Blennow, K., Ryan N., Lashley T., Hanrieder J.* “Chemical traits of vascular amyloid pathology in rare familial dementias” 2022 J Neurochem. 163(3):233-246 (Cover)
• 8, Kouterapu, Ge J., Dulewicz M, Szadziewska A., Zetterberg H., Blennow, K., Ryan N., Lashley T., Schöll M., Savas JN, Hanrieder J.* “Chemical signatures delineate heterogeneous amyloid plaque populations across the Alzheimer’s disease spectrum” 2025 Nature Communications 16(1):3889
• 9, Michno, W., Stringer, K. S., Enzlein, T., Passarelli, M. K., Escrig S., Blennow, K., Zetterberg, H., Meibom, A., Hopf, C., Edwards, F. A., Hanrieder, J.* “Following spatial Aβ plaque aggregation dynamics in evolving Alzheimer’s pathology by imaging stable isotope labelling kinetics (iSILK)” Science Advances 2021 7(25):eabg4855. PMC8208724
• 10, Wood J, Wong E, Joghee R, Balbaa A, Vitanova KS, Vanshoiack A, Phelan S-LJ, Launchbury F, Desai S, Tripathi T, Hanrieder J, Cummings DM, Hardy J, Edwards FA “Upregulation of Trem2 expression occurs exclusively on microglial contact with plaques.” Cell Reports 2022 41(8):111686
• 11, Wood J, Dulewicz M, Ge J., Szadziewska A., Desai S, Kouterapu S.,  Blennow K, Zetterberg H, Cummings DM, Savas JN, Edwards FA, Hanrieder J*, “Deciphering Plaque Age Through Metabolic Labelling: Insights into Structural maturation, Gene Expression, and Toxicity” 2025 Nature Communications 16(1):8170