Amyloid-related imaging abnormalities: manifestations, metrics and mechanisms
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Cathepsin B prevents cell death by fragmentation and destruction of pathological amyloid fibrils
Amyloid fibrils cause organ and tissue dysfunction in numerous severe diseases. Despite the prevalence and severity of amyloidoses, there is still no effective and safe anti-amyloid therapy. This study investigates the impact of cysteine protease cathepsin B (CTSB) on amyloids associated with Alzheimer’s and Parkinson’s diseases, hemodialysis, and lysozyme amyloidosis. We analyzed the effect of CTSB on the size, structure, and proteotoxicity of amyloid fibrils formed from alpha-synuclein, abeta peptide (1-42), insulin, and lysozyme using a combination of spectroscopic, microscopic, electrophoretic, and colorimetric methods. Our comprehensive research revealed a dual effect of CTSB on amyloid fibrils. Firstly, CTSB induced amyloid fragmentation while preserving their ordered morphology, and, secondly, it “loosened” the tertiary structure of amyloids and reduced the regularity of the secondary structure. This dual mechanism of action was universal across fibrils associated with different pathologies, although the disruption efficacy and predominant type of degradation products depended on the amyloids’ structure, size, and clustering. Notably, CTSB-induced irreversible degradation significantly reduced the toxicity for immortalized and primary cell lines of low-clustered fibrils, such as alpha-synuclein amyloids associated with Parkinson’s disease. These findings enhance our understanding of how endogenous CTSB may regulate amyloid content at the molecular level in different neuropathologies. In addition, our results suggest the potential of CTSB as a component of anti-amyloid drugs in combination with agents that enhance the accessibility of proteolytic sites within amyloid clots and reduce these clusters stability.
Subcellular proteomics and iPSC modeling uncover reversible mechanisms of axonal pathology in Alzheimer’s disease
Dystrophic neurites (also termed axonal spheroids) are found around amyloid deposits in Alzheimer’s disease (AD), where they impair axonal electrical conduction, disrupt neural circuits and correlate with AD severity. Despite their importance, the mechanisms underlying spheroid formation remain incompletely understood. To address this, we developed a proximity labeling approach to uncover the proteome of spheroids in human postmortem and mouse brains. Additionally, we established a human induced pluripotent stem cell (iPSC)-derived AD model enabling mechanistic investigation and optical electrophysiology. These complementary approaches revealed the subcellular molecular architecture of spheroids and identified abnormalities in key biological processes, including protein turnover, cytoskeleton dynamics and lipid transport. Notably, the PI3K/AKT/mTOR pathway, which regulates these processes, was activated in spheroids. Furthermore, phosphorylated mTOR levels in spheroids correlated with AD severity in humans. Notably, mTOR inhibition in iPSC-derived neurons and mice ameliorated spheroid pathology. Altogether, our study provides a multidisciplinary toolkit for investigating mechanisms and therapeutic targets for axonal pathology in neurodegeneration.
Isoaspartate-containing galanin in rat hypothalamus
The isoaspartate residue is a spontaneous, time-dependent post-translational modification (PTM) of proteins and peptides, associated with in vivo protein aggregation and changes in molecule lifetime. While this is considered a slow modification impacting long lived proteins, surprisingly, we observed this PTM at high levels within the relatively short-lived neuropeptide galanin (Gal). The combination of liquid chromatography-trapped ion mobility mass spectrometry and protein Isoaspartyl methyltransferase assays demonstrated that 20 ± 2% of the mature Gal contain L-Isoaspartate residue in the hypothalamus of Rattus norvegicus. Aspartate in Gal isomerizes spontaneously under mildly acidic conditions within 48 h in vitro, much faster than previously assumed. Gal with the L-isoaspartate PTM significantly enhanced fibril formation. Transmission electron microscopy revealed differences in morphology of fibrils formed by D17Isoasparte Gal compared to the unmodified peptide. Observed characteristics of D17Isoasparte Gal suggest a potential mechanism for the development of in vivo Gal fibril deposits previously reported in the brain.
Categorizing robots by performance fitness into the tree of robots
Robots are typically classified based on specific morphological features, like their kinematic structure. However, a complex interplay between morphology and intelligence shapes how well a robot performs processes. Just as delicate surgical procedures demand high dexterity and tactile precision, manual warehouse or construction work requires strength and endurance. These process requirements necessitate robot systems that provide a level of performance fitting the process. In this work, we introduce the tree of robots as a taxonomy to bridge the gap between morphological classification and process-based performance. It classifies robots based on their fitness to perform, for example, physical interaction processes. Using 11 industrial manipulators, we constructed the first part of the tree of robots based on a carefully deduced set of metrics reflecting fundamental robot capabilities for various industrial physical interaction processes. Through significance analysis, we identified substantial differences between the systems, grouping them via an expectation-maximization algorithm to create a fitness-based robot classification that is open for contributions and accessible.
In vivo surface-enhanced Raman scattering techniques: nanoprobes, instrumentation, and applications
Surface-enhanced Raman scattering (SERS) has emerged as a powerful tool in various biomedical applications, including in vivo imaging, diagnostics, and therapy, largely due to the development of near-infrared (NIR) active SERS substrates. This review provides a comprehensive overview of SERS-based applications in vivo, focusing on key aspects such as the design considerations for SERS nanoprobes and advancements in instrumentation. Topics covered include the development of NIR SERS substrates, Raman label compounds (RLCs), protective coatings, and the conjugation of bioligands for targeted imaging and therapy. The review also discusses microscope-based configurations such as scanning, widefield imaging, and fiber-optic setups. Recent advances in using SERS nanoprobes for in vivo sensing, diagnostics, biomolecule screening, multiplex imaging, intraoperative guidance, and multifunctional cancer therapy are highlighted. The review concludes by addressing challenges in the clinical translation of SERS nanoprobes and outlines future directions, emphasizing opportunities for advancing biomedical research and clinical applications.
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