Amyloid fibrils are thread-like protein aggregates with a core region formed from repetitive arrays of beta-sheets oriented parallel to the fibril axis. Such structures were first recognized in clinical disorders, but more recently have also been linked to a variety of non-pathogenic phenomena ranging from the transfer of genetic information to synaptic changes associated with memory. The observation that many proteins can convert into similar structures in vitro has suggested that this ability is a generic feature of polypeptide chains. Here we have probed the nature of the amyloid structure by monitoring hydrogen/deuterium exchange in fibrils formed from an SH3 domain using a combination of nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry. The results reveal that under the conditions used in this study, exchange is dominated by a mechanism of dissociation and re-association that results in the recycling of molecules within the fibril population. This insight into the dynamic nature of amyloid fibrils, and the ability to determine the parameters that define this behaviour, have important implications for the design of therapeutic strategies directed against amyloid disease.
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http://dx.doi.org/10.1038/nature03986 | DOI Listing |
Mol Neurobiol
January 2025
School of Pharmacy, Chengdu Medical College, Chengdu, 610500, PR China.
Alzheimer's disease (AD) is a prominent neurodegenerative disorder affecting the central nervous system in the elderly. Current understanding of AD primarily centers on the gradual decline in cognitive and memory functions, believed to be influenced by factors including mitochondrial dysfunction, β-amyloid aggregation, and neuroinflammation. Emerging research indicates that neuroinflammation plays a significant role in the development of AD, with the inflammasome potentially mediating inflammatory responses that contribute to neurodegeneration.
View Article and Find Full Text PDFJ Control Release
January 2025
Paris Brain Institute, ICM, Inserm U1127, CNRS UMR 7225, Sorbonne University, 75013 Paris, France.
Unlabelled: Blood-brain barrier opening with ultrasound can potentiate drug efficacy in the treatment of brain pathologies and also provides therapeutic effects on its own. It is an innovative tool to transiently, repeatedly and safely open the barrier, with studies showing beneficial effects in both preclinical models for Alzheimer's disease and recent clinical studies. The first preclinical and clinical work has mainly shown a decrease in amyloid burden in mice models and in patients.
View Article and Find Full Text PDFNeurobiol Dis
January 2025
Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada; Neurology Division, Department of Medicine, University of Saskatchewan, Saskatoon, SK S7N 0X8, Canada. Electronic address:
RNA binding protein dysfunction is a pathogenic feature of multiple neurological diseases, including multiple sclerosis (MS). Neurodegeneration (the loss of, or damage to neurons and axons) is the primary driver of disease progression in MS. Herein, we utilized a novel, neuron-specific model of neurodegeneration by transducing primary mouse neurons with mutant forms of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) identified from MS patients, including one within the M9-nuclear localization sequence of hnRNP A1 (A1(P275S)) and a second in the prion-like domain of hnRNP A1 (A1(F263S)) to test the hypothesis that neuronal hnRNP A1 dysfunction drives neurodegeneration in MS.
View Article and Find Full Text PDFBiomaterials
January 2025
144 College St, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada. Electronic address:
The development of disease-modifying therapeutics for Alzheimer's disease remains challenging due to the complex pathology and the presence of the blood-brain barrier. Previously we have described the investigation of a brain-penetrating multifunctional bioreactive nanoparticle system capable of remodeling the hypoxic and inflammatory brain microenvironment and reducing beta-amyloid plaques improving cognitive function in a mouse model of Alzheimer's disease. Despite the linkage of hypoxia and inflammation to metabolic alteration, the effects of this system on modulating cerebral glucose metabolism, mitochondrial activity and synaptic function remained to be elucidated.
View Article and Find Full Text PDFJ Med Chem
January 2025
Bioorganic Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Jakkur P.O., Bengaluru 560064, Karnataka, India.
Nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domain (PYD)-containing protein 3 (NLRP3) form an inflammasome by assembling with apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1 that plays a pivotal role in various neurodegenerative diseases such as Alzheimer's and Parkinson diseases. We designed native peptides derived from the PYDs of NLRP3 and ASC based on their interfacial interaction to inhibit NLRP3 inflammasome formation. Screening revealed that , derived from NLRP3, inhibits inflammasome activation.
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