A cysteine proteinase inhibitor has been purified by affinity chromatography from the liver of buffalo. Liver cystatin is subjected to incubation at low pH with co-solvent TFE, where we have studied the effect on the conformation, activity and tendency to form aggregates or fibrils. ANS fluorescence was used to study conformational changes. The fibril formation and aggregation was studied using ThT assay, CD, FTIR and fluorescence spectroscopy. At pH 3.0 there was no fibril formation though aggregates were formed but in presence of TFE fibrils appeared. At pH 2.0 and 1.0, TFE induced rapid fibril formation compared to only acid induced state as assessed by Thioflavin T (ThT) fluorescence.TFE stabilized each of the three acid induced intermediates at predenaturational concentrations (20%) and accelerated fibril formation. Solvent conditions had a profound effect on the tendency of liver cystatin to produce fibrils and aggregation.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1971565 | DOI Listing |
Background: Phosphorylated tau proteins accumulate in pathological aggregates which define neurodegenerative tauopathies, including Alzheimer's disease (AD). Insight into the early stages of tau polymerization/aggregation, including early hyperphosphorylation events, is critical for identification of biomarkers of incipient disease as well as novel therapy targets.
Method: We analyzed postmortem tissue sections of hippocampus from AD cases and middle frontal gyrus from non-AD cases with mainly 4R tau isoforms (progressive supranuclear palsy, PSP; corticobasal degeneration, CBD; aging related tau astrogliopathy, ARTAG) or 3R tau (Pick's disease, PiD).
Alzheimers Dement
December 2024
University of Southern California, Los Angeles, CA, USA.
Background: Higher order regulation of autonomic function is maintained by cortical and subcortical interconnected regions within the brain, collectively referred to as the central autonomic network (CAN) (Benarroch, 1993). Despite the well-established relationship between autonomic dysfunction and AD (Femminella et al., 2014) the relationship between CAN functional connectivity and biomarkers of AD, such as Ab ratio, remains unexplored.
View Article and Find Full Text PDFBackground: The accumulation of hyperphosphorylated, aggregated tau in neurons is one of the hallmarks of Alzheimer's disease (AD). Recent work in structural biology has solved the structure of tau fibrils in several tauopathies and found that the structure of the tau fibrils varies between diseases, but fibril structure is conserved among patients within the same disease, suggesting fibril structure relates to its pathogenicity. Tau fibrils derived from AD brain (AD PHFs) seed AD-like pathology in wild-type mice, yet efforts to recapitulate this seeding with recombinant fibrils have failed.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Cognition Therapeutics, Inc, Pittsburgh, PA, USA.
Background: The sigma-2 receptor (S2R) modulator CT1812 is a first-in-class investigational therapeutic, currently in Phase 2 clinical trials for Alzheimer's disease (AD). Preclinical and clinical studies have shown that CT1812 displaces Aβ oligomers from synapses and clears them from the brain into the cerebrospinal fluid, restoring cognitive performance in a transgenic mouse model of AD. To investigate the mechanism of action of CT1812 and enable biomarker discovery, a phosphoproteomic analysis of CSF samples from SHINE-A was performed.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, Shanghai, China.
Background: Dementia patients often have several co-existing diseases, whereas the specific temporality and development patterns between them remain uncertain.
Method: Based on the multicenter, community-based prospective UK Biobank, enriched disease diagnoses were extracted from hospital admission linkage, along with basic demographic information and individual genome data from the baseline visit. We constructed disease trajectory before dementia utilizing the phenome-wide association analysis to firstly filter potential precursors, the directional test to select temporal disease pairs, and conditional logistic regression to finally quantify association strength.
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