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Jörg Hanrieder
Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sweden
Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, United Kingdom
Mass spectrometry has gained increasing prominence in biomedical research providing as new apogee of molecular imaging. The technique combines features of molecular histology with the high dimensionality and specificity warranted by mass spectrometry at low um resolution. Our group has been advancing MS imaging approaches for chemical neuroimaging, specifically to understand neurodegenerative disease pathomechanisms.
Here, it is of critical importance to our understanding of Alzheimer’s disease (AD) pathology, to determine how key pathological factors including beta-amyloid (Aβ) plaque formation are interconnected and implicated in nerve cell death, clinical symptoms, and disease progression. Exactly how Aβ plaque formation begins and how the ongoing plaque deposition proceeds and initiates subsequent neurotoxic mechanisms is not well understood.
The primary aim of our research is to elucidate the biochemical processes underlying early Aβ plaque formation in brain tissue.
We developed a chemical imaging pardigm including hyperspectral microscopy and mass spectrometry imaging that allows to delineate vivo Aβ build up and deposition at cellular length scales. Specifically, we advanced the integration of conformation sensitive hyperspectral mass spectrometry with MSI modalities to elucidate plaque morphology associated changes in Aβ signatures.
We further pioneered means for amyloid chronology based on imaging stable isotope labelling kinetics (iSILK). Here, novel genetic AD mice are labelled metabolically with stable isotopes to follow the fate of aggregating Aβ species from before and throughout the earliest events of precipitating plaque pathology.
This allowed to visualize Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. These data, for the first time, describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.
The results from these studies bring considerable novel information about the deposition mechanism of Aβ and its toxic interactions with the surrounding. This will open up for developing tailored strategies to affect AD pathology prior to any neurodegenerative mechanisms as well as to develop new biomarkers for AD.
Jack Wood1,2, Katie Stringer1,2, Junyue Ge1, Eugenia Wong2, Srinivas Koutarapu1, Damian M. Cummings2, Frances A. Edwards2 and Jörg Hanrieder1
1Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal Hospital, Mölndal, Sweden
2Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK
Spatial transcriptomics overcomes limitations of RNA sequencing techniques to allow transcriptomic data to be collected from set regions of an imaged tissue section. This is particularly important for Alzheimer’s disease (AD) research as pathologies of AD are spatial specific and unevenly distributed. I will present two projects that use spatial transcriptomics to investigate transcriptomic changes immediately around amyloid plaques in mouse models of AD.
The first explores changes in microglial gene expression with decreasing distance to amyloid plaques. The findings reports that the majority of plaque induced genes, a recently published gene set, depend on direct contact of microglia with plaque. Furthermore, crossing in the AD-risk mutation Trem2R47H inhibited the plaque-induced expression of genes involved in phagocytic and lysosomal degradation.
The second study demonstrates the integration of spatial transcriptomics with imaging mass spectrometry and stable isotope feeding paradigms to mark Aβ species from initial plaque formation. This approach allows us to track the age of amyloid plaques and correlate it with transcriptomic changes, identifying which genes react to new plaques how they change as plaques age.
Alicja Szadziewska1, Srinivas Koutarapu1, Maciej Dulewicz1, Przemyslaw R Kac1, Anne Hiniker2, Denis Smirnov3, Henrik Zetterberg1,4-8, Douglas Galasko2, Kaj Blennow1,5, Jörg Hanrieder1,4
1Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Sweden
2Department of Pathology, University of California San Diego, San Diego, USA
3Department of Neurosciences, University of California San Diego, San Diego, USA
4Department of Neurodegenerative Disease, Institute of Neurology, University College London, United Kingdom
5Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Sweden
6UK Dementia Research Institute, University College London, United Kingdom
7Hong Kong Center for Neurodegenerative Diseases, China
8Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, USA
Alzheimer's disease (AD), accounting for 60–80% of dementia cases worldwide, characterized by neurofibrillary tangles (NFT) made of tau protein. The study focuses on the tau fragment, tau368, cleaved by asparagine endopeptidase (AEP) and found in cerebrospinal fluid (CSF). A new Simoa assay (Single Molecule Array) has been developed to measure CSF tau368 levels. Previous studies show that the ratio of tau fragments with truncated C-terminus, particularly when compared to total tau, shows a robust correlation with the uptake of tau PET tracers. The primary goal of this project is to use immunofluorescence to understand tau368 morphology in the human brain and its relationship with disease severity.
The research involved analyzing post-mortem tissue from the hippocampus and frontal cortex alongside CSF, employing multiplex immunofluorescence to elucidate tangle maturation patterns. Luminescent Conjugated Oligothiophenes (LCOs) serve to identify amyloid plaques and neurofibrillary tangles. Tau pathology was detailed using specific antibodies, including for Tau368 and pTau217, highlighting maturation patterns. Tau368 levels in CSF were measured using an in-house Simoa assay.
Findings showed Tau368 accumulation in various tau aggregates (e.g., pretangles, NFTs, ghost tangles). We observed negative correlation between tau368-positive tangles in the hippocampus subiculum and CSF tau368/t-tau levels (r=−0.99; p=0.010). Hippocampal tau368-positive tangles correlate positively with BRAAK staging (r=0.72; p=0.04) and THAL staging (r=0.80, p=0.021).
This study advances our understanding of tau pathology in AD, emphasizing the role of tau polymorphs and epitope expression in disease progression.
