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Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology 2.0

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 (31 May 2022) | Viewed by 21386

Special Issue Editor

Dr. Maria Laura Giuffrida

E-Mail Website
Guest Editor
Italian National Research Council, Institute of Crystallography (IC), 95126 Catania, Italy
Interests: Alzheimer’s disease; molecular neurobiology; amyloid-β; primary cortical neurons; signal transduction; BDNF; insulin and insulin-like growth factor signaling in Alzheimer's disease; HSP60; Aβ and copper; small molecules and peptide inhibitors of Aβ aggregation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

This Special Issue is the continuation of our previous Special Issue "Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology".

Alzheimer’s disease (AD) is still an incurable disease with an incidence that is expected to increase in the near future. In previous decades, the pathophysiology of AD has been extensively investigated. Several approaches have been employed to disclose the molecular mechanisms underlying the cellular dysfunctions typically observed in AD. From in vitro and in vivo findings, we have learned that Aβ oligomers (AβOs), rather than Aβ fibrils, are mainly responsible for the effects leading to neurodegeneration. They have shown a better correlation with the severity of the disease and, in line with this observation, were found to induce synaptic dysfunction in the early stage of the disease, promote oxidative stress, and interfere with the activation of important cellular receptors. However, besides these unquestionable roles of Aβ oligomers, the primary cause of Aβ over-production and aggregation is far from being completely clarified.

Moreover, after initial evidence that Aβ monomers are innocuous, an increasing amount of data have indicated that Aβ may have important physiological roles in neuronal activity. A more comprehensive understanding of Aβ functions, from physiology to the occurrence of AD pathological conditions, could contribute to the refinement of pharmacological interventions and the design of new drug candidates.

Most AD drugs have been projected to block Aβ production or aggregation. However, the targeting of all Aβ species, including monomers, might be the reason for the continuous failure of clinical trials. The recent encouraging results of antibodies which preferentially bind to toxic AβOs seem to support this view.

The aim of this Special Issue of IJMS is to collect, in a broader perspective, scientific papers as well as reviews of the current literature, that deal with amyloid beta peptide function in health and/or disease. All original works that look at the role of Aβ within and beyond the disease and contribute to the improvement of the molecular understanding of Alzheimer’s disease are welcome.

Dr. Maria Laura Giuffrida
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • Aβ monomers
  • Aβ oligomers
  • signal transduction
  • neuroprotection
  • anti- Aβ therapy

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Published Papers (8 papers)

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Editorial

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4 pages, 196 KiB  
Editorial
Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology
by Maria Laura Giuffrida
Int. J. Mol. Sci. 2023, 24(9), 7913; https://doi.org/10.3390/ijms24097913 - 26 Apr 2023
Viewed by 1141
Abstract
Alzheimer’s disease (AD) represents one of the most challenging disorders, and despite having been widely studied since its first identification, resolutive treatments are still far out of reach [...] Full article
(This article belongs to the Special Issue Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology 2.0)

Research

Jump to: Editorial

21 pages, 6013 KiB  
Article
Allosteric Binding Sites of Aβ Peptides on the Acetylcholine Synthesizing Enzyme ChAT as Deduced by In Silico Molecular Modeling
by Anurag TK Baidya, Amit Kumar, Rajnish Kumar and Taher Darreh-Shori
Int. J. Mol. Sci. 2022, 23(11), 6073; https://doi.org/10.3390/ijms23116073 - 28 May 2022
Cited by 22 | Viewed by 2208
Abstract
The native function of amyloid-β (Aβ) peptides is still unexplored. However, several recent reports suggest a prominent role of Aβ peptides in acetylcholine homeostasis. To clarify this role of Aβ, we have reported that Aβ peptides at physiological concentrations can directly enhance the [...] Read more.
The native function of amyloid-β (Aβ) peptides is still unexplored. However, several recent reports suggest a prominent role of Aβ peptides in acetylcholine homeostasis. To clarify this role of Aβ, we have reported that Aβ peptides at physiological concentrations can directly enhance the catalytic efficiency of the key cholinergic enzyme, choline acetyltransferase (ChAT), via an allosteric interaction. In the current study, we further aimed to elucidate the underlying ChAT-Aβ interaction mechanism using in silico molecular docking and dynamics analysis. Docking analysis suggested two most probable binding clusters on ChAT for Aβ40 and three for Aβ42. Most importantly, the docking results were challenged with molecular dynamic studies of 100 ns long simulation in triplicates (100 ns × 3 = 300 ns) and were analyzed for RMSD, RMSF, RoG, H-bond number and distance, SASA, and secondary structure assessment performed together with principal component analysis and the free-energy landscape diagram, which indicated that the ChAT-Aβ complex system was stable throughout the simulation time period with no abrupt motion during the evolution of the simulation across the triplicates, which also validated the robustness of the simulation study. Finally, the free-energy landscape analysis confirmed the docking results and demonstrated that the ChAT-Aβ complexes were energetically stable despite the unstructured nature of C- and N-terminals in Aβ peptides. Overall, this study supports the reported in vitro findings that Aβ peptides, particularly Aβ42, act as endogenous ChAT-Potentiating-Ligand (CPL), and thereby supports the hypothesis that one of the native biological functions of Aβ peptides is the regulation of acetylcholine homeostasis. Full article
(This article belongs to the Special Issue Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology 2.0)
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25 pages, 11697 KiB  
Article
An Essential Role for Alzheimer’s-Linked Amyloid Beta Oligomers in Neurodevelopment: Transient Expression of Multiple Proteoforms during Retina Histogenesis
by Samuel C. Bartley, Madison T. Proctor, Hongjie Xia, Evelyn Ho, Dong S. Kang, Kristen Schuster, Maíra A. Bicca, Henrique S. Seckler, Kirsten L. Viola, Steven M. Patrie, Neil L. Kelleher, Fernando G. De Mello and William L. Klein
Int. J. Mol. Sci. 2022, 23(4), 2208; https://doi.org/10.3390/ijms23042208 - 17 Feb 2022
Cited by 7 | Viewed by 2897
Abstract
Human amyloid beta peptide (Aβ) is a brain catabolite that at nanomolar concentrations can form neurotoxic oligomers (AβOs), which are known to accumulate in Alzheimer’s disease. Because a predisposition to form neurotoxins seems surprising, we have investigated whether circumstances might exist where AβO [...] Read more.
Human amyloid beta peptide (Aβ) is a brain catabolite that at nanomolar concentrations can form neurotoxic oligomers (AβOs), which are known to accumulate in Alzheimer’s disease. Because a predisposition to form neurotoxins seems surprising, we have investigated whether circumstances might exist where AβO accumulation may in fact be beneficial. Our investigation focused on the embryonic chick retina, which expresses the same Aβ as humans. Using conformation-selective antibodies, immunoblots, mass spectrometry, and fluorescence microscopy, we discovered that AβOs are indeed present in the developing retina, where multiple proteoforms are expressed in a highly regulated cell-specific manner. The expression of the AβO proteoforms was selectively associated with transiently expressed phosphorylated Tau (pTau) proteoforms that, like AβOs, are linked to Alzheimer’s disease (AD). To test whether the AβOs were functional in development, embryos were cultured ex ovo and then injected intravitreally with either a beta-site APP-cleaving enzyme 1 (BACE-1) inhibitor or an AβO-selective antibody to prematurely lower the levels of AβOs. The consequence was disrupted histogenesis resulting in dysplasia resembling that seen in various retina pathologies. We suggest the hypothesis that embryonic AβOs are a new type of short-lived peptidergic hormone with a role in neural development. Such a role could help explain why a peptide that manifests deleterious gain-of-function activity when it oligomerizes in the aging brain has been evolutionarily conserved. Full article
(This article belongs to the Special Issue Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology 2.0)
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10 pages, 2891 KiB  
Article
Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer’s Disease Rat Model: A Proof-of-Concept Study
by Daniele de Paula Faria, Larissa Estessi de Souza, Fabio Luis de Souza Duran, Carlos Alberto Buchpiguel, Luiz Roberto Britto, José Alexandre de Souza Crippa, Geraldo Busatto Filho and Caroline Cristiano Real
Int. J. Mol. Sci. 2022, 23(3), 1076; https://doi.org/10.3390/ijms23031076 - 19 Jan 2022
Cited by 13 | Viewed by 2857
Abstract
An early and persistent sign of Alzheimer’s disease (AD) is glucose hypometabolism, which can be evaluated by positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Cannabidiol has demonstrated neuroprotective and anti-inflammatory properties but has not been evaluated by PET imaging in [...] Read more.
An early and persistent sign of Alzheimer’s disease (AD) is glucose hypometabolism, which can be evaluated by positron emission tomography (PET) with 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Cannabidiol has demonstrated neuroprotective and anti-inflammatory properties but has not been evaluated by PET imaging in an AD model. Intracerebroventricular (icv) injection of streptozotocin (STZ) is a validated model for hypometabolism observed in AD. This proof-of-concept study evaluated the effect of cannabidiol treatment in the brain glucose metabolism of an icv-STZ AD model by PET imaging. Wistar male rats received 3 mg/kg of STZ and [18F]FDG PET images were acquired before and 7 days after STZ injection. Animals were treated with intraperitoneal cannabidiol (20 mg/kg—STZ–cannabidiol) or saline (STZ–saline) for one week. Novel object recognition was performed to evaluate short-term and long-term memory. [18F]FDG uptake in the whole brain was significantly lower in the STZ–saline group. Voxel-based analysis revealed a hypometabolism cluster close to the lateral ventricle, which was smaller in STZ–cannabidiol animals. The brain regions with more evident hypometabolism were the striatum, motor cortex, hippocampus, and thalamus, which was not observed in STZ–cannabidiol animals. In addition, STZ–cannabidiol animals revealed no changes in memory index. Thus, this study suggests that cannabidiol could be an early treatment for the neurodegenerative process observed in AD. Full article
(This article belongs to the Special Issue Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology 2.0)
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14 pages, 3533 KiB  
Article
Specific Mutations in Aph1 Cause γ-Secretase Activation
by Hikari Watanabe, Chika Yoshida, Masafumi Hidaka, Tomohisa Ogawa, Taisuke Tomita and Eugene Futai
Int. J. Mol. Sci. 2022, 23(1), 507; https://doi.org/10.3390/ijms23010507 - 3 Jan 2022
Cited by 5 | Viewed by 2355
Abstract
Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutations within the catalytic subunit of γ-secretase, [...] Read more.
Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutations within the catalytic subunit of γ-secretase, presenilin 1 (PS1). FAD mutations of PS1 cause partial loss-of-function and decrease the cleavage activity. Activating mutations, which have the opposite effect of FAD mutations, are important for studying Aβ production. Aph1 is a regulatory subunit of γ-secretase; it is presumed to function as a scaffold of the complex. In this study, we identified Aph1 mutations that are active in the absence of nicastrin (NCT) using a yeast γ-secretase assay. We analyzed these Aph1 mutations in the presence of NCT; we found that the L30F/T164A mutation is activating. When introduced in mouse embryonic fibroblasts, the mutation enhanced cleavage. The Aph1 mutants produced more short and long Aβs than did the wild-type Aph1, without an apparent modulatory function. The mutants did not change the amount of γ-secretase complex, suggesting that L30F/T164A enhances catalytic activity. Our results provide insights into the regulatory function of Aph1 in γ-secretase activity. Full article
(This article belongs to the Special Issue Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology 2.0)
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23 pages, 38907 KiB  
Article
Differential Clearance of Aβ Species from the Brain by Brain Lymphatic Endothelial Cells in Zebrafish
by Yun-Mi Jeong, Jae-Geun Lee, Hyun-Ju Cho, Wang Sik Lee, Jinyoung Jeong and Jeong-Soo Lee
Int. J. Mol. Sci. 2021, 22(21), 11883; https://doi.org/10.3390/ijms222111883 - 2 Nov 2021
Cited by 4 | Viewed by 2492
Abstract
The failure of amyloid beta (Aβ) clearance is a major cause of Alzheimer’s disease, and the brain lymphatic systems play a crucial role in clearing toxic proteins. Recently, brain lymphatic endothelial cells (BLECs), a non-lumenized lymphatic cell in the vertebrate brain, was identified, [...] Read more.
The failure of amyloid beta (Aβ) clearance is a major cause of Alzheimer’s disease, and the brain lymphatic systems play a crucial role in clearing toxic proteins. Recently, brain lymphatic endothelial cells (BLECs), a non-lumenized lymphatic cell in the vertebrate brain, was identified, but Aβ clearance via this novel cell is not fully understood. We established an in vivo zebrafish model using fluorescently labeled Aβ42 to investigate the role of BLECs in Aβ clearance. We discovered the efficient clearance of monomeric Aβ42 (mAβ42) compared to oligomeric Aβ42 (oAβ42), which was illustrated by the selective uptake of mAβ42 by BLECs and peripheral transport. The genetic depletion, pharmacological inhibition via the blocking of the mannose receptor, or the laser ablation of BLECs resulted in the defective clearance of mAβ42. The treatment with an Aβ disaggregating agent facilitated the internalization of oAβ42 into BLECs and improved the peripheral transport. Our findings reveal a new role of BLECs in the differential clearance of mAβ42 from the brain and provide a novel therapeutic strategy based on promoting Aβ clearance. Full article
(This article belongs to the Special Issue Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology 2.0)
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13 pages, 1049 KiB  
Communication
Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice
by Torsten Hoffmann, Jens-Ulrich Rahfeld, Mathias Schenk, Falk Ponath, Koki Makioka, Birgit Hutter-Paier, Inge Lues, Cynthia A. Lemere and Stephan Schilling
Int. J. Mol. Sci. 2021, 22(21), 11791; https://doi.org/10.3390/ijms222111791 - 30 Oct 2021
Cited by 10 | Viewed by 3474
Abstract
Compelling evidence suggests that pyroglutamate-modified Aβ (pGlu3-Aβ; AβN3pG) peptides play a pivotal role in the development and progression of Alzheimer’s disease (AD). Approaches targeting pGlu3-Aβ by glutaminyl cyclase (QC) inhibition (Varoglutamstat) or monoclonal antibodies (Donanemab) are currently in clinical development. Here, we aimed [...] Read more.
Compelling evidence suggests that pyroglutamate-modified Aβ (pGlu3-Aβ; AβN3pG) peptides play a pivotal role in the development and progression of Alzheimer’s disease (AD). Approaches targeting pGlu3-Aβ by glutaminyl cyclase (QC) inhibition (Varoglutamstat) or monoclonal antibodies (Donanemab) are currently in clinical development. Here, we aimed at an assessment of combination therapy of Varoglutamstat (PQ912) and a pGlu3-Aβ-specific antibody (m6) in transgenic mice. Whereas the single treatments at subtherapeutic doses show moderate (16–41%) but statistically insignificant reduction of Aβ42 and pGlu-Aβ42 in mice brain, the combination of both treatments resulted in significant reductions of Aβ by 45–65%. Evaluation of these data using the Bliss independence model revealed a combination index of ≈1, which is indicative for an additive effect of the compounds. The data are interpreted in terms of different pathways, in which the two drugs act. While PQ912 prevents the formation of pGlu3-Aβ in different compartments, the antibody is able to clear existing pGlu3-Aβ deposits. The results suggest that combination of the small molecule Varoglutamstat and a pE3Aβ-directed monoclonal antibody may allow a reduction of the individual compound doses while maintaining the therapeutic effect. Full article
(This article belongs to the Special Issue Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology 2.0)
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18 pages, 4386 KiB  
Article
Protective Role of a Donepezil-Huprine Hybrid against the β-Amyloid (1-42) Effect on Human Erythrocytes
by Pablo Zambrano, Mario Suwalsky, Malgorzata Jemiola-Rzeminska, María José Gallardo-Nelson, Kazimierz Strzalka and Diego Muñoz-Torrero
Int. J. Mol. Sci. 2021, 22(17), 9563; https://doi.org/10.3390/ijms22179563 - 3 Sep 2021
Cited by 9 | Viewed by 2292
Abstract
Aβ(1-42) peptide is a neurotoxic agent strongly associated with the etiology of Alzheimer’s disease (AD). Current treatments are still of very low effectiveness, and deaths from AD are increasing worldwide. Huprine-derived molecules have a high affinity towards the enzyme acetylcholinesterase (AChE), act as [...] Read more.
Aβ(1-42) peptide is a neurotoxic agent strongly associated with the etiology of Alzheimer’s disease (AD). Current treatments are still of very low effectiveness, and deaths from AD are increasing worldwide. Huprine-derived molecules have a high affinity towards the enzyme acetylcholinesterase (AChE), act as potent Aβ(1-42) peptide aggregation inhibitors, and improve the behavior of experimental animals. AVCRI104P4 is a multitarget donepezil-huprine hybrid that improves short-term memory in a mouse model of AD and exerts protective effects in transgenic Caenorhabditis elegans that express Aβ(1-42) peptide. At present, there is no information about the effects of this compound on human erythrocytes. Thus, we considered it important to study its effects on the cell membrane and erythrocyte models, and to examine its protective effect against the toxic insult induced by Aβ(1-42) peptide in this cell and models. This research was developed using X-ray diffraction and differential scanning calorimetry (DSC) on molecular models of the human erythrocyte membrane constituted by lipid bilayers built of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE). They correspond to phospholipids representative of those present in the external and internal monolayers, respectively, of most plasma and neuronal membranes. The effect of AVCRI104P4 on human erythrocyte morphology was studied by scanning electron microscopy (SEM). The experimental results showed a protective effect of AVCRI104P4 against the toxicity induced by Aβ(1-42) peptide in human erythrocytes and molecular models. Full article
(This article belongs to the Special Issue Amyloid β and Alzheimer’s Disease: Molecular Updates from Physiology to Pathology 2.0)
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