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Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Title
Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Creator
Kaczmarek, Julia A.
Date
2023
Description
The loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment...
Show moreThe loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment. An effector molecule of the disease, amyloid-beta (Aβ), has been observed to interact with lipid membranes, but its relevance to mitochondrial membranes containing CL remained elusive. The present study investigated if the presence of CL modulated the insertion of adsorbed helical amyloid beta (Aβ14-40) into model mitochondrial membranes, and if this effect was more pronounced for its N-terminus or C-terminus. I conducted a coarse-grained computer simulation using well-tempered metadynamics to traverse the free energy landscape that maps the translocation of Aβ14-40. Insertion into CL-containing bilayers created larger local membrane deformations and modulated the location of the transition path but had an inconclusive impact on the free energy cost of translocation. Since the generation of toxic calcium-permeable pores depends on the insertion of Aβ into the bilayer, the loss of CL seen in AD may prime the inner mitochondrial membrane for pore formation, but more research is needed to pursue this hypothesis.
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Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Title
Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Creator
Kaczmarek, Julia A.
Date
2023
Description
The loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment...
Show moreThe loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment. An effector molecule of the disease, amyloid-beta (Aβ), has been observed to interact with lipid membranes, but its relevance to mitochondrial membranes containing CL remained elusive. The present study investigated if the presence of CL modulated the insertion of adsorbed helical amyloid beta (Aβ14-40) into model mitochondrial membranes, and if this effect was more pronounced for its N-terminus or C-terminus. I conducted a coarse-grained computer simulation using well-tempered metadynamics to traverse the free energy landscape that maps the translocation of Aβ14-40. Insertion into CL-containing bilayers created larger local membrane deformations and modulated the location of the transition path but had an inconclusive impact on the free energy cost of translocation. Since the generation of toxic calcium-permeable pores depends on the insertion of Aβ into the bilayer, the loss of CL seen in AD may prime the inner mitochondrial membrane for pore formation, but more research is needed to pursue this hypothesis.
Show less
Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Title
Cardiolipin Modulates the Insertion of Adsorbed Helical Amyloid Beta Peptide Into Model Mitochondrial Membranes
Creator
Kaczmarek, Julia A.
Date
2023
Description
The loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment...
Show moreThe loss of mitochondrial phospholipid cardiolipin (CL) may play a role in both the pathogenesis of Alzheimer's Disease (AD) and its treatment. An effector molecule of the disease, amyloid-beta (Aβ), has been observed to interact with lipid membranes, but its relevance to mitochondrial membranes containing CL remained elusive. The present study investigated if the presence of CL modulated the insertion of adsorbed helical amyloid beta (Aβ14-40) into model mitochondrial membranes, and if this effect was more pronounced for its N-terminus or C-terminus. I conducted a coarse-grained computer simulation using well-tempered metadynamics to traverse the free energy landscape that maps the translocation of Aβ14-40. Insertion into CL-containing bilayers created larger local membrane deformations and modulated the location of the transition path but had an inconclusive impact on the free energy cost of translocation. Since the generation of toxic calcium-permeable pores depends on the insertion of Aβ into the bilayer, the loss of CL seen in AD may prime the inner mitochondrial membrane for pore formation, but more research is needed to pursue this hypothesis.
Show less