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Advances in the Search for Protective Agents against Amyloid β-Induced Brain Degeneration

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Dear Colleagues,

The enhanced production of neurotoxic amyloid β peptides in the brain has been reported in the context of brain neurodegenerative processes and neurological disorders. Neurotoxic amyloid β peptides can be produced by neurons and/or reactive astrocytes generated due to the brain inflammation observed in neurodegenerative processes. The small oligomers of neurotoxic amyloid β peptides are chiefly responsible for the neurotoxicity of amyloid β peptides in the brain. This Special Issue focuses on agents that afford protection against the rise of neurotoxic amyloid β peptides in the intracellular and extracellular spaces of the brain, which could find potential applications in improved therapies aiming to delay or prevent brain neurodegeneration. These agents can be endogenous biomolecules that scavenge nanomolar concentrations of neurotoxic amyloid β peptides, a primary defense barrier, but also compounds that attenuate the production of these peptides or antagonize the neuronal dysfunctions induced by neurotoxic amyloid β peptides. Eventually, this leads to neuronal death, such as the loss of synaptic functions, the dysregulation of neuronal intracellular calcium homeostasis, mitochondrial dysfunction, oxidative stress, and excitotoxicity.

Prof. Dr. Carlos Gutiérrez-Merino
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Keywords

amyloid β-peptides
endogenous scavengers
antagonists
Alzheimer’s disease
neurological disorders
brain neurodegeneration

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Review

18 pages, 894 KiB

Open AccessReview

Brain Hydrophobic Peptides Antagonists of Neurotoxic Amyloid β Peptide Monomers/Oligomers–Protein Interactions

by Carlos Gutierrez-Merino

Int. J. Mol. Sci. 2023, 24(18), 13846; https://doi.org/10.3390/ijms241813846 - 08 Sep 2023

Cited by 1 | Viewed by 797

Abstract

Amyloid β (Aβ) oligomers have been linked to Alzheimer’s disease (AD) pathogenesis and are the main neurotoxic forms of Aβ. This review focuses on the following: (i) the Aβ(1–42):calmodulin interface as a model for the design of antagonist Aβ peptides and its limitations; (ii) proteolytic degradation as the major source of highly hydrophobic peptides in brain cells; and (iii) brain peptides that have been experimentally demonstrated to bind to Aβ monomers or oligomers, Aβ fibrils, or Aβ plaques. It is highlighted that the hydrophobic amino acid residues of the COOH-terminal segment of Aβ(1–42) play a key role in its interaction with intracellular protein partners linked to its neurotoxicity. The major source of highly hydrophobic endogenous peptides of 8–10 amino acids in neurons is the proteasome activity. Many canonical antigen peptides bound to the major histocompatibility complex class 1 are of this type. These highly hydrophobic peptides bind to Aβ and are likely to be efficient antagonists of the binding of Aβ monomers/oligomers concentrations in the nanomolar range with intracellular proteins. Also, their complexation with Aβ will protect them against endopeptidases, suggesting a putative chaperon-like physiological function for Aβ that has been overlooked until now. Remarkably, the hydrophobic amino acid residues of Aβ responsible for the binding of several neuropeptides partially overlap with those playing a key role in its interaction with intracellular protein partners that mediates its neurotoxicity. Therefore, these latter neuropeptides are also potential candidates to antagonize Aβ peptides binding to target proteins. In conclusion, the analysis performed in this review points out that hydrophobic endogenous brain neuropeptides could be valuable biomarkers to evaluate the risk of the onset of sporadic AD, as well as for the prognosis of AD. Full article

(This article belongs to the Special Issue Advances in the Search for Protective Agents against Amyloid β-Induced Brain Degeneration)

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Advances in the Search for Protective Agents against Amyloid β-Induced Brain Degeneration

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