Hybrid Multifunctional Modulators Inhibit Multifaceted Aβ Toxicity and Prevent Mitochondrial Damage
Abstract
Amyloid beta (Aβ) aggregation is the key trait responsible for the pathological devastation caused by Alzheimer’s disease (AD). Among the various pathways of multifaceted toxicity exhibited by Aβ aggregates in neuronal cells, generation of reactive oxygen species (ROS) by Aβ-Cu II complex and mitochondrial damage are prominent. Aβ interferes with mitochondrial transport channels, causing mitochondrial dysfunction. Herein, we present nontoxic hybrid multifunctional modulators (HMMs, TGR86–88) developed by integrating the structural and functional features of the metal chelating aggregation modulator, clioquinol (Clq), and the antioxidant epigallocatechin gallate (EGCG). Detailed biophysical and docking studies show that TGR86 interacts with Aβ and efficiently modulates both metal-dependent and metal-independent Aβ aggregation. TGR86 complexes with Cu II, arrests its redox cycle, and thereby prevents the generation of ROS. The antioxidant nature of the HMMs effectively prevents DNA damage and protein oxidation. TGR86 rescued PC12 cells from Aβ-induced neurotoxicity by preventing the generation of ROS and foiling the interaction of toxic Aβ species with mitochondria, thereby averting its damage. These key attributes make TGR86 a potential candidate to develop therapeutics for the multifactorial Aβ toxicity in Alzheimer’s disease.
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GHKSrVSrFSr(P6) chelates Cu2 released from Aβ42-Cu2 and protects plasmid DNA and other cells from ROS and metal-induced toxicity.
“Another example includes multifunctional peptidomimetic GHKSrVSrFSr(P6), which chelates Cu2 released from Aβ42-Cu2 and protects plasmid DNA and other cells from ROS and metal induced toxicity [122].”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [122]
Peptidomimetics bind to the central hydrophobic core recognition sites of tau and Aβ aggregates and prevent further progression of their deposition.
“The peptidomimetics reacts or bind to these regions and prevents further progression of their deposition.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [122]
TGR86 forms additional hydrogen bonds with Asn27, Lys28 and Ser26 of Aβ, due to which it showed maximum activity, and it increases cell viability.
“TGR86forms additional hydrogen bonds with Asn27, Lys28 and Ser26 region of Aβ due to which it showed maximum activity. TGR86 also increases cell viability [122].”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [122]
Among HMMs, TGR86 gave the best results for inhibiting Aβ by sequestering it from copper ions, followed by TGR88, TGR87 and Clq.
“Among them, TGR86 gave best results for inhibiting Aβ by sequestering it from copper ions followed by TGR88, TGR87 and Clq.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [122]
Hybrid multifunctional modulators (HMMs) inhibit aggregation of Aβ associated with metal ions and prevent mitochondrial damage.
“HMMs inhibit aggregation of Aβ associated with metal ions and prevent mitochondrial damage.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [122]
Thy-KSrVSrFSr(P5), a multifunctional peptidomimetic based on the KLVFF recognition site, is a potent inhibitor of Aβ and stimulates Aβ degradation by activating autophagy in a yeast model.
“Thy-KSrVSrFSr(P5) multifunctional peptidomimetic (based on KLVFF recognition site) is a potent inhibitor of Aβ. It stimulates the degradation of Aβ by activating autophagy mechanism in a yeast model.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [122]
Some peptidomimetics dissolve pre-formed tau and Aβ aggregates.
“Some of them also dissolve the pre formed aggregates.”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [122]
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- Authors
- Rajasekhar, K., Mehta, K., & Govindaraju, T.
- Affiliations
- Jawaharlal Nehru Centre for Advanced Scientific Research (IN)
- Corresponding author
- Govindaraju, Thimmaiah
- Venue
- ACS Chemical Neuroscience
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-03-20
- Volume
- 9
- Issue
- 6
- Pages
- 1432-1440
- ISSN
- 1948-7193 (ISSN-L)
- OpenAlex
- W2793975280
- Cited by
- 69
- References
- 55
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 8 · 2023: 3 · 2022: 12 · 2021: 9 · 2020: 12 · 2019: 9 · 2018: 6
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- ACS Chemical Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Science and Technology, Ministry of Science and Technology (DST/SJF/CSA-02/2015-2016)
- Jawaharlal Nehru Centre for Advanced Scientific Research
- Sheikh Saqr Laboratory
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta aggregation, Alzheimer's disease, clioquinol, epigallocatechin gallate, mitochondrial damage, metal chelation, antioxidants, neuroprotection, PC12 cells, DNA damage, protein oxidation, molecular docking
- MeSH terms
- Alzheimer Disease, Animals, Antioxidants, Chelating Agents, Clioquinol, Mitochondria, Peptide Fragments, Reactive Oxygen Species, Oxidative Stress, Rats
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