A Review of the Current Status of Disease-Modifying Therapies and Prevention of Alzheimer’s Disease

Parums, Dinah V.

doi:10.12659/msm.945091

Cited by 1 publication

(3 citation statements)

References 36 publications

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“…Antioxidation + AChE inhibition 7 BHT-CNS-11 Antioxidation + tau fibril disaggregation 8 1 An isoform of glycogen synthase kinase 3 (GSK3) linked to tau phosphorylation in tauopathy [43]. 2 Acetylcholinesterase (AChE) linked to degraded acetylcholine (AChE) [44]. 3 Eliminates free radicals caused by oxidative stress [38].…”

Section: Bht-e20mentioning

confidence: 99%

“…1 Cryo-EM structure from human AD brain autopsy tissues as given by Seidler et al [13]. 2 Same as above but with samples incubated with EGCG for 3 h as given by Seidler et al [13]. 3 Cryo-EM structure from human AD brain autopsy tissues as given by Fitzpatrick et al [11].…”

Section: Dimer Tetramermentioning

confidence: 99%

“…Despite the increase in cases of AD in recent years, its complex mechanisms remain unclear, and no effective treatments to slow or reverse its progression have been found. A few current treatments include Lecanemab, aducanumab, donepezil, galantamine, rivastigmine, and memantine [ 2 , 3 ]. Of these, Lecanemab and aducanumab are the only ones used to clear Aβ plaques, while the remaining four focus on treating symptoms.…”

Section: Introductionmentioning

confidence: 99%

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Exploring Tau Fibril-Disaggregating and Antioxidating Molecules Binding to Membrane-Bound Amyloid Oligomers Using Machine Learning-Enhanced Docking and Molecular Dynamics

Segura,

Santos,

Flores

et al. 2024

Molecules

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Intracellular tau fibrils are sources of neurotoxicity and oxidative stress in Alzheimer’s. Current drug discovery efforts have focused on molecules with tau fibril disaggregation and antioxidation functions. However, recent studies suggest that membrane-bound tau-containing oligomers (mTCOs), smaller and less ordered than tau fibrils, are neurotoxic in the early stage of Alzheimer’s. Whether tau fibril-targeting molecules are effective against mTCOs is unknown. The binding of epigallocatechin-3-gallate (EGCG), CNS-11, and BHT-CNS-11 to in silico mTCOs and experimental tau fibrils was investigated using machine learning-enhanced docking and molecular dynamics simulations. EGCG and CNS-11 have tau fibril disaggregation functions, while the proposed BHT-CNS-11 has potential tau fibril disaggregation and antioxidation functions like EGCG. Our results suggest that the three molecules studied may also bind to mTCOs. The predicted binding probability of EGCG to mTCOs increases with the protein aggregate size. In contrast, the predicted probability of CNS-11 and BHT-CNS-11 binding to the dimeric mTCOs is higher than binding to the tetrameric mTCOs for the homo tau but not for the hetero tau–amylin oligomers. Our results also support the idea that anionic lipids may promote the binding of molecules to mTCOs. We conclude that tau fibril-disaggregating and antioxidating molecules may bind to mTCOs, and that mTCOs may also be useful targets for Alzheimer’s drug design.

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