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Background: Genetic studies have established that loss of function SORL1 gene variants are associated with Alzheimer's disease (AD). SORL1 encodes an endosomal trafficking receptor, SORLA, which regulates endosomal protein recycling through its interaction with the retromer core complex (consisting of VPS26, VPS35 and VPS29). Deficits in the levels and function of the SORLA-retromer complex are thought to underlie AD.
View Article and Find Full Text PDFBackground: There are no cures for Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by elevation of beta-amyloid and tau proteins besides neuronal death and causing cognitive impairment. Phosphodiesterase 5 (PDE5) is a cyclic guanosine monophosphate-degrading enzyme involved in numerous biological pathways including those relevant to memory formation. PDE5 inhibition offers the potential to attenuate AD progression by acting at the downstream level of beta-amyloid and tau elevation.
View Article and Find Full Text PDFGamma-secretases play a pivotal role in the generation of Aβ peptides. Mutations in these enzymes that cause early-onset, autosomal dominant AD shift Aβ production towards generation of longer peptides. We have recently shown that the mutation-induced shifts in the ratio of short-to-long Aβ peptides not only inform about mutation pathogenicity but also allow experimental prediction of the age at dementia onset.
View Article and Find Full Text PDFDementia Care Research and Psychosocial Factors.
Alzheimers Dement
December 2024
Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
Background: To support informal caregivers of persons with dementia (PwD), it is fundamental to understand how objective and subjective indicators of care burden are interrelated. This study used psychometric network analyses to explore care burden indicators and extend current models of care in informal caregivers of PwDs.
Methods: Baseline data from an intervention study of 170 informal caregivers of community-dwelling PwDs was used.
Activation and Reactivity of the Deubiquitinylase OTU Cezanne-2 from MD Simulations and QM/MM Calculations.
J Chem Inf Model
January 2025
Molecular Simulations and Design Group, Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstrasse 1, 39106 Magdeburg, Germany.
Cezanne-2 (Cez2) is a deubiquitinylating (DUB) enzyme involved in the regulation of ubiquitin-driven cellular signaling and selectively targets Lys11-linked polyubiquitin chains. As a representative member of the ovarian tumor (OTU) subfamily DUBs, it performs cysteine proteolytic isopeptide bond cleavage; however, its exact catalytic mechanism is not yet resolved. In this work, we used different computational approaches to get molecular insights into the Cezanne-2 catalytic mechanism.
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