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

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (20 March 2025) | Viewed by 4049

Special Issue Editor

Prof. Dr. Carlos Gutiérrez-Merino

E-Mail Website
Guest Editor
Institute of Molecular Pathology Biomarkers, University of Extremadura, 06006 Badajoz, Spain
Interests: tissue degeneration; biomaker; amyloid β-calmodulin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

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
Guest Editor

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Keywords

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

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Published Papers (3 papers)

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Research

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32 pages, 13231 KiB  
Article
Combination of Epigallocatechin-3-Gallate and Tramiprosate Prevent Accumulation of Intracellular Aβ and Dysfunctional Autophagy–Lysosomal Pathway at Earliest Stage of Transdifferentiation of Mesenchymal Stromal Cells into PSEN1 E280A Cholinergic-like Neurons
by Viviana Soto-Mercado, Miguel Mendivil-Perez, Marlene Jimenez-Del-Rio and Carlos Velez-Pardo
Int. J. Mol. Sci. 2025, 26(8), 3756; https://doi.org/10.3390/ijms26083756 - 16 Apr 2025
Viewed by 244
Abstract
Familial Alzheimer’s disease (FAD) caused by presenilin 1 (PSEN1) E280A induces the aberrant accumulation of intracellular Aβ (iAβ) in cholinergic-like neurons (ChLNs). How early iAβ accumulates in the development of ChLNs is still unknown. Consequently, the timing of appropriate therapeutic approaches against FAD [...] Read more.
Familial Alzheimer’s disease (FAD) caused by presenilin 1 (PSEN1) E280A induces the aberrant accumulation of intracellular Aβ (iAβ) in cholinergic-like neurons (ChLNs). How early iAβ accumulates in the development of ChLNs is still unknown. Consequently, the timing of appropriate therapeutic approaches against FAD is unclear. To determine the earliest iAβ in PSEN1 E280A ChLNs, flow cytometry and immunofluorescence microscopy were used to follow the development of menstrual mesenchymal stromal cells (MenSCs) into ChLNs (proliferation marker Ki67, cluster of differentiation 73 (CD73), neuronal nuclei (NeuN) marker, choline acetyl transferase (ChAT)), the kinetics of iAβ accumulation, and the simultaneous evaluation of other associated markers (e.g., DJ-1C106-SO3; lysosomes; phosphatidylethanolamine-conjugated microtubule-associated protein 1A/1B light chain 3, LC3-II; cleaved caspase 3 (CC3)) at 0, 1, 3, 5, and 7 days. To reverse the PSEN1 E280A phenotype, we used rapamycin (RAP), verubecestat (VER), compound E (CE), epigallocatechin-3-gallate (EGCG), and tramiprosate (TM) in WT and mutant ChLNs. We found that PSEN1 E280A did not induce significant differences in the NeuN marker and ChAT in MenSCs transitioning to ChLNs. The iAβ accumulates at the earliest cholinergic developmental stage from day 0 (18%, at MenSCs stage) to day 7 (46%, at ChLNs stage), i.e., iAβ increased +156% in mutant compared to WT cells (1–6%). A significant increase in DJ-1C106-SO3 occurs only at day 7 (+250%). While neither CC3 (0–1%) nor lysosomes were different between WT and mutant cells at any time point, a stepwise increase in autophagosome accumulation was observed from day 3 (15%) to day 7 (79%), i.e., +427%, in mutant cells. While neither RAP, VER, nor CE was able to completely reduce all PSEN1 E280A-induced markers in ChLNs, the combination of EGCG and TM was more effective in removing these markers than EGCG and TM alone in PSEN1 E280A ChLNs. Given that this investigation is based on a single menstrual blood sample from WT and PSEN1 E280A, our results should be considered exploratory. Larger sample sizes are needed. 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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14 pages, 6691 KiB  
Article
Protective Effects of Ambroxol on Aβ and α-Synuclein-Induced Neurotoxicity Through Glucocerebrosidase Activation in HT-22 Hippocampal Neuronal Cells
by Sheng-Chieh Lin, Ching-Chi Chang, Sing-Hua Tsou, Pai-Yi Chiu, Ju-Fang Cheng, Hui-Chih Hung, Wei-Jen Chen, Ying-Jui Ho and Chih-Li Lin
Int. J. Mol. Sci. 2024, 25(22), 12114; https://doi.org/10.3390/ijms252212114 - 12 Nov 2024
Viewed by 1653
Abstract
Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing with amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting a critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to [...] Read more.
Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disorder marked by the accumulation of α-synuclein (αSyn), often co-existing with amyloid β (Aβ) pathology. Current treatments are largely symptomatic, highlighting a critical need for disease-modifying therapies. Evidence suggests that αSyn aggregates contribute to neuronal death in DLB, particularly when exacerbated by Aβ. Given the role of autophagy in clearing misfolded proteins, exploring agents that promote this pathway is essential for developing effective treatments. Ambroxol (AMBX), a mucolytic drug, has demonstrated potential in activating glucocerebrosidase (GCase), an enzyme that enhances lysosomal function and facilitates the autophagic clearance of toxic protein aggregates, including αSyn. This study aims to evaluate AMBX’s neuroprotective effects in a cellular model of DLB, with the goal of identifying new therapeutic agents that target the underlying pathology of DLB. In this study, HT-22 hippocampal neuronal cells were exposed to αSyn and Aβ, followed by AMBX treatment. Our results showed that AMBX significantly improved cell viability and reduced apoptosis in cells co-treated with αSyn and Aβ. Additionally, AMBX restored GCase activity, promoted autophagy, and reduced oxidative stress, which in turn mitigated αSyn aggregation and phosphorylation. These findings suggest that by activating GCase and enhancing autophagy, AMBX may help alleviate DLB-associated neurodegeneration. This study underscores the potential of AMBX as a therapeutic agent for DLB and supports further investigation in animal models and clinical trials to validate its efficacy in neurodegenerative disease contexts. 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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Review

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18 pages, 894 KiB  
Review
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 - 8 Sep 2023
Cited by 2 | Viewed by 1499
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; [...] Read more.
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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