Chemical traits of cerebral amyloid angiopathy in familial British‐, Danish‐, and <scp>non‐Alzheimer</scp>ʼs dementias

Michno, Wojciech; Koutarapu, Srinivas; Camacho, Rafael; Toomey, Christina E.; Stringer, Katie M.; Minta, Karolina; Ge, Junyue; Jha, Durga; Fernández-Rodrı́guez, Julia; Brinkmalm, Gunnar; Zetterberg, Henrik; Blennow, Kaj; Ryan, Natalie S.; Lashley, Tammaryn; Hanrieder, Jörg

doi:10.1111/jnc.15694

Cited by 7 publications

(9 citation statements)

References 42 publications

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“…Finally, our results show that the Aβ pattern observed for coarse grain plaques was generally very similar to that of CAA deposits. This is interesting as CAA load has also been associated with clinical dementia both in AD but also familial British and Danish dementia ( Michno et al 2022 ). Indeed, a vascular component in CG formation has previously been proposed, where CGs were found to display a characteristic increase in vascular and capillary pathology markers including norrin, laminin and collagen IV, respectively ( Boon et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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Chemical signatures delineate heterogeneous amyloid plaque populations across the Alzheimer’s disease spectrum

Koutarapu,

Ge,

Dulewicz

et al. 2024

Preprint

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Amyloid plaque deposition is recognized as the primary pathological hallmark of Alzheimer’s disease(AD) that precedes other pathological events and cognitive symptoms. Plaque pathology represents itself with an immense polymorphic variety comprising plaques with different stages of amyloid fibrillization ranging from diffuse to fibrillar, mature plaques. The association of polymorphic Aβ plaque pathology with AD pathogenesis, clinical symptoms and disease progression remains unclear. Advanced chemical imaging tools, such as functional amyloid microscopy combined with MALDI mass spectrometry imaging (MSI), are now enhanced by deep learning algorithms. This integration allows for precise delineation of polymorphic plaque structures and detailed identification of their associated Aβ compositions. We here set out to make use of these tools to interrogate heterogenic plaque types and their associated biochemical architecture. Our findings reveal distinct Aβ signatures that differentiate diffuse plaques from fibrilized ones, with the latter showing substantially higher levels of Aβx-40. Notably, within the fibrilized category, we identified a distinct subtype known as coarse-grain plaques. Both in sAD and fAD brain tissue, coarse grain plaques contained more Aβx-40 and less Aβx-42 compared with cored plaques. The coarse grain plaques in both sAD and fAD also showed higher levels of neuritic content including paired helical filaments (PHF-1)/phosphorylated phospho Tau-immunopositive neurites. Finally, the Aβ peptide content in coarse grain plaques resembled that of vascular Aβ deposits (CAA) though with relatively higher levels of Aβ1-42 and pyroglutamated Aβx-40 and Aβx-42 species in coarse grain plaques. This is the first of its kind study on spatialin situbiochemical characterization of different plaque morphotypes demonstrating the potential of the correlative imaging techniques used that further increase the understanding of heterogeneous AD pathology. Linking the biochemical characteristics of amyloid plaque polymorphisms with various AD etiologies and toxicity mechanisms is crucial. Understanding the connection between plaque structure and disease pathogenesis can enhance our insights. This knowledge is particularly valuable for developing and advancing novel, amyloid-targeting therapeutics.

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Section: Discussionmentioning

confidence: 99%

“…with clinical dementia both in AD but also familial British and Danish dementia (Michno et al 2022). Indeed, a vascular component in CG formation has previously been proposed, where…”

Section: [Cg Vs Caa]mentioning

confidence: 97%

Chemical signatures delineate heterogeneous amyloid plaque populations across the Alzheimer’s disease spectrum

Koutarapu,

Ge,

Dulewicz

et al. 2024

Preprint

Self Cite

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“…An example was to enable correlative imaging with mass spectroscopy imaging modalities. 57 Inherent to the development of any new measurement is the corresponding development in techniques for analysis, with significant resources often needed to create in-house software/platforms that allow quantitation/correlation/outputs. Bioimaging CFs, and more recently Bioimage Analysis CFs, are important drivers of such developments and software solutions that often start as ad hoc prototypes to solve immediate problems of internal projects, usually develop into open-source tools, 58,59 and sometimes evolve into widely popular and essential packages used in the scientific community (ec-CLEM, 60 TrackMate 61 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, integration of additional nonimaging modalities (such as mass spectrometry) or ‘biomedical’ imaging modalities such as µCT and µPET can enrich datasets and allow measurement and correlation of (for example) the evolution of target/metabolic fluxes in living organisms over time. An example was to enable correlative imaging with mass spectroscopy imaging modalities 57 …”

Section: Discussionmentioning

confidence: 99%

Innovating in a bioimaging core through instrument development

Munck,

De Bo,

Cawthorne

et al. 2024

Journal of Microscopy

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Developing devices and instrumentation in a bioimaging core facility is an important part of the innovation mandate inherent in the core facility model but is a complex area due to the required skills and investments, and the impossibility of a universally applicable model. Here, we seek to define technological innovation in microscopy and situate it within the wider core facility innovation portfolio, highlighting how strategic development can accelerate access to innovative imaging modalities and increase service range, and thus maintain the cutting edge needed for sustainability. We consider technology development from the perspective of core facility staff and their stakeholders as well as their research environment and aim to present a practical guide to the ‘Why, When, and How’ of developing and integrating innovative technology in the core facility portfolio.Core facilities need to innovate to stay up to date. However, how to carry out the innovation is not very obvious. One area of innovation in imaging core facilities is the building of optical setups. However, the creation of optical setups requires specific skill sets, time, and investments. Consequently, the topic of whether a core facility should develop optical devices is discussed as controversial. Here, we provide resources that should help get into this topic, and we discuss different options when and how it makes sense to build optical devices in core facilities. We discuss various aspects, including consequences for staff and the relation of the core to the institute, and also broaden the scope toward other areas of innovation.

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“…ITM2C (Integral membrane protein 2C) also known as BRI3 has been shown to interact with APP and act as a negative regulator of Aβ production 55 . Its homolog BRI2 (ITM2B) is known to cause cerebral amyloid angiopathy in familial British and Danish dementias 56 . In contrast, SFRP1 (secreted-frizzled-related protein 1) interferes with anti-amyloidogenic processing of APP via metalloprotease ADAM10 leading to generation of toxic Aβ products 57 .…”

Section: Discussionmentioning

confidence: 99%

Proteomic Changes in the Human Cerebrovasculature in Alzheimer’s Disease and Related Tauopathies Linked to Peripheral Biomarkers in Plasma and Cerebrospinal Fluid

Wojtas,

Dammer,

Guo

et al. 2024

Preprint

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Dysfunction of the neurovascular unit stands as a significant pathological hallmark of Alzheimer's disease (AD) and age-related neurodegenerative diseases. Nevertheless, detecting vascular changes in the brain within bulk tissues has proven challenging, limiting our ability to characterize proteomic alterations from less abundant cell types. To address this challenge, we conducted quantitative proteomic analyses on both bulk brain tissues and cerebrovascular-enriched fractions from the same individuals, encompassing cognitively unimpaired control, progressive supranuclear palsy (PSP), and AD cases. Protein co-expression network analysis identified modules unique to the cerebrovascular fractions, specifically enriched with pericytes, endothelial cells, and smooth muscle cells. Many of these modules also exhibited significant correlations with amyloid plaques, cerebral amyloid angiopathy (CAA), and/or tau pathology in the brain. Notably, the protein products within AD genetic risk loci were found concentrated within modules unique to the vascular fractions, consistent with a role of cerebrovascular deficits in the etiology of AD. To prioritize peripheral AD biomarkers associated with vascular dysfunction, we assessed the overlap between differentially abundant proteins in AD cerebrospinal fluid (CSF) and plasma with a vascular-enriched network modules in the brain. This analysis highlighted matrisome proteins, SMOC1 and SMOC2, as being increased in CSF, plasma, and brain. Immunohistochemical analysis revealed SMOC1 deposition in both parenchymal plaques and CAA in the AD brain, whereas SMOC2 was predominantly localized to CAA. Collectively, these findings significantly enhance our understanding of the involvement of cerebrovascular abnormalities in AD, shedding light on potential biomarkers and molecular pathways associated with CAA and vascular dysfunction in neurodegenerative diseases.

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Chemical traits of cerebral amyloid angiopathy in familial British‐, Danish‐, and non‐Alzheimerʼs dementias

Cited by 7 publications

References 42 publications

Chemical signatures delineate heterogeneous amyloid plaque populations across the Alzheimer’s disease spectrum

Chemical signatures delineate heterogeneous amyloid plaque populations across the Alzheimer’s disease spectrum

Innovating in a bioimaging core through instrument development

Proteomic Changes in the Human Cerebrovasculature in Alzheimer’s Disease and Related Tauopathies Linked to Peripheral Biomarkers in Plasma and Cerebrospinal Fluid

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