P1-245: MOLECULAR DYNAMIC MODELLING OF TWO TREM2 MUTATIONS REVEAL KEY STRUCTURAL SIMILARITIES AND PROBABLE FUNCTIONAL IMPACT IN ALZHEIMER'S DISEASE

2006 ◽  
Vol 14 (7S_Part_7) ◽  
pp. P372-P372
Author(s):  
Georgina E. Menzies ◽  
Rebecca Sims ◽  
Julie Williams
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamic ◽  
Dynamic Modelling ◽  
Functional Impact

Molecular dynamic studies of amyloid-beta interactions with curcumin and Cu2+ ions

2015 ◽  
Vol 69 (9) ◽  
Author(s):  
Stanislav Kozmon ◽  
Igor Tvaroška
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Transition Metals ◽  
Metal Ions ◽  
Molecular Dynamic ◽  
Amyloid Beta ◽  
Md Simulations ◽  
Aβ Peptide ◽  
Dynamic Studies

AbstractAmyloid-beta (Aβ) peptide readily forms aggregates that are associated with Alzheimer’s disease. Transition metals play a key role in this process. Recently, it has been shown that curcumin (CUA), a polyphenolic phytochemical, inhibits the aggregation of Aβ peptide. However, interactions of Aβ peptide with metal ions or CUA are not entirely clear. In this work, molecular dynamics (MD) simulations were carried out to clear the nature of interactions between the 42-residue Aβ peptide (Aβ-42) and Cu

scholarly journals Effect of Amyloid-β Monomers on Lipid Membrane Mechanical Parameters–Potential Implications for Mechanically Driven Neurodegeneration in Alzheimer’s Disease

2020 ◽  
Vol 22 (1) ◽  
pp. 18
Author(s):  
Dominik Drabik ◽  
Grzegorz Chodaczek ◽  
Sebastian Kraszewski
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Wave Propagation ◽  
Molecular Dynamic ◽  
Lipid Membrane ◽  
Flicker Noise ◽  
Alternative Hypothesis ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Dynamic Studies

Alzheimer’s disease (AD) is a neurodegenerative disease that results in memory loss and the impairment of cognitive skills. Several mechanisms of AD’s pathogenesis were proposed, such as the progressive accumulation of amyloid-β (Aβ) and τ pathology. Nevertheless, the exact neurodegenerative mechanism of the Aβ remains complex and not fully understood. This paper proposes an alternative hypothesis of the mechanism based on maintaining the neuron membrane’s mechanical balance. The incorporation of Aβ decreases the lipid membrane’s elastic properties, which eventually leads to the impairment of membrane clustering, disruption of mechanical wave propagation, and change in gamma oscillations. The first two disrupt the neuron’s ability to function correctly while the last one decreases sensory encoding and perception enabling. To begin discussing this mechanical-balance hypothesis, we measured the effect of two selected peptides, Aβ-40 and Aβ-42, as well as their fluorescently labeled modification, on membrane mechanical properties. The decrease of bending rigidity, consistent for all investigated peptides, was observed using molecular dynamic studies and experimental flicker-noise techniques. Additionally, wave propagation was investigated with molecular dynamic studies in membranes with and without incorporated neurodegenerative peptides. A change in membrane behavior was observed in the membrane system with incorporated Aβ.

scholarly journals The Alzheimer’s disease protective P522R variant of PLCG2, consistently enhances stimulus-dependent PLCγ2 activation, depleting substrate and altering cell function

2020 ◽  
Author(s):  
Emily Maguire ◽  
Georgina E. Menzies ◽  
Thomas Phillips ◽  
Michael Sasner ◽  
Harriet M. Williams ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Function ◽  
Association Studies ◽  
Dynamic Modelling ◽  
Genome Wide Association Studies ◽  
Aβ Oligomers ◽  
Induced Pluripotent ◽  
Receptor Ligation

AbstractRecent genome-wide association studies of Alzheimer’s disease (AD) have identified variants implicating immune pathways in disease development. A rare coding variant of PLCG2, which encodes PLCγ2, shows a significant protective effect for AD (rs72824905, P522R, P=5.38×10−10, Odds Ratio = 0.68). Molecular dynamic modelling of the PLCγ2-R522 variant, situated within the auto-inhibitory domain of PLCγ2, suggests a structural change to the protein. Through CRISPR-engineering we have generated novel PLCG2-R522 harbouring human induced pluripotent cell lines (hiPSC) and a mouse knockin model, neither of which exhibits alterations in endogenous PLCG2 expression. Mouse microglia and macrophages and hiPSC-derived microglia-like cells with the R522 mutation, all demonstrate a consistent non-redundant hyperfunctionality in the context of normal expression of other PLC isoforms. This signalling alteration manifests as enhanced cellular Ca2+ store release (∼20-40% increase) in response to physiologically-relevant stimuli (e.g. Fc receptor ligation and Aβ oligomers). This hyperfunctionality resulted in increased PIP2 depletion in the cells with the PLCγ2-R522 variant after exposure to stimuli and reduced basal detection of PIP2 levels in vivo. These PLCγ2-R522 associated abnormalities resulted in impairments to phagocytosis (fungal and bacterial particles) and enhanced endocytosis (Aβ oligomers and dextran). PLCγ2 sits downstream of disease relevant pathways, such as TREM2 and CSF1R and alterations in its activity, direct impacts cell function, which in the context of the inherent drugability of enzymes such as PLCγ2, raise the prospect of manipulation of PLCγ2 as a therapeutic target in Alzheimer’s Disease.

scholarly journals Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mubashir Hassan ◽  
Sara Zahid ◽  
Hany Alashwal ◽  
Andrzej Kloczkowski ◽  
Ahmed A. Moustafa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
Molecular Dynamic ◽  
Conformational Changes ◽  
Mapk Pathway ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Downstream Signaling ◽  
Interactive Behavior

AbstractProteins are tiny players involved in the activation and deactivation of multiple signaling cascades through interactions in cells. The TNFR1 and MADD interact with each other and mediate downstream protein signaling pathways which cause neuronal cell death and Alzheimer’s disease. In the current study, a molecular docking approach was employed to explore the interactive behavior of TNFR1 and MADD proteins and their role in the activation of downstream signaling pathways. The computational sequential and structural conformational results revealed that Asp400, Arg58, Arg59 were common residues of TNFR1 and MADD which are involved in the activation of downstream signaling pathways. Aspartic acid in negatively charged residues is involved in the biosynthesis of protein. However, arginine is a positively charged residue with the potential to interact with oppositely charged amino acids. Furthermore, our molecular dynamic simulation results also ensured the stability of the backbone of TNFR1 and MADD death domains (DDs) in binding interactions. This DDs interaction mediates some conformational changes in TNFR1 which leads to the activation of mediators proteins in the cellular signaling pathways. Taken together, a better understanding of TNFR1 and MADD receptors and their activated signaling cascade may help treat Alzheimer’s disease. The death domains of TNFR1 and MADD could be used as a novel pharmacological target for the treatment of Alzheimer’s disease by inhibiting the MAPK pathway.

Sign in / Sign up

Export Citation Format

Share Document