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18 pages, 5232 KiB

Open AccessArticle

Amyloid-Beta Peptides Trigger Premature Functional and Gene Expression Alterations in Human-Induced Neurons

by Ana Raquel Melo de Farias, Alexandre Pelletier, Lukas Cruz Carvalho Iohan, Orthis Saha, Amélie Bonnefond, Philippe Amouyel, Fabien Delahaye, Jean-Charles Lambert and Marcos R. Costa

Biomedicines 2023, 11(9), 2564; https://doi.org/10.3390/biomedicines11092564 - 18 Sep 2023

Cited by 2 | Viewed by 1096

Abstract

Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid-beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade hypothesis postulates that deposition of Aβ peptides is the [...] Read more.

Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly, characterized by the presence of amyloid-beta (Aβ) plaques, neurofibrillary tangles, neuroinflammation, synapse loss and neurodegeneration in the brain. The amyloid cascade hypothesis postulates that deposition of Aβ peptides is the causative agent of AD pathology, but we still lack comprehensive understanding of the molecular mechanisms connecting Aβ peptides to neuronal dysfunctions in AD. In this work, we investigate the early effects of Aβ peptide accumulation on the functional properties and gene expression profiles of human-induced neurons (hiNs). We show that hiNs acutely exposed to low concentrations of both cell-secreted Aβ peptides or synthetic Aβ_1–42 exhibit alterations in the frequency of calcium transients suggestive of increased neuronal excitability. Using single-cell RNA sequencing, we also show that cell-secreted Aβ up-regulates the expression of several synapse-related genes and down-regulates the expression of genes associated with metabolic stress mainly in glutamatergic neurons and, to a lesser degree, in GABAergic neurons and astrocytes. These neuronal alterations correlate with activation of the SEMA5, EPHA and NECTIN signaling pathways, which are important regulators of synaptic plasticity. Altogether, our findings indicate that slight elevations in Aβ concentrations are sufficient to elicit transcriptional changes in human neurons, which can contribute to early alterations in neural network activity. Full article

(This article belongs to the Special Issue Amyloid Pathology: Cellular Mechanism and Therapy Targets)

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27 pages, 9894 KiB

Open AccessArticle

Structural Specificity of Polymorphic Forms of α-Synuclein Amyloid

by Irena Roterman, Katarzyna Stapor and Leszek Konieczny

Biomedicines 2023, 11(5), 1324; https://doi.org/10.3390/biomedicines11051324 - 29 Apr 2023

Cited by 1 | Viewed by 1010

Abstract

The structural transformation producing amyloids is a phenomenon that sheds new light on the protein folding problem. The analysis of the polymorphic structures of the α-synuclein amyloid available in the PDB database allows analysis of the amyloid-oriented structural transformation itself, but also the [...] Read more.

The structural transformation producing amyloids is a phenomenon that sheds new light on the protein folding problem. The analysis of the polymorphic structures of the α-synuclein amyloid available in the PDB database allows analysis of the amyloid-oriented structural transformation itself, but also the protein folding process as such. The polymorphic amyloid structures of α-synuclein analyzed employing the hydrophobicity distribution (fuzzy oil drop model) reveal a differentiation with a dominant distribution consistent with the micelle-like system (hydrophobic core with polar shell). This type of ordering of the hydrophobicity distribution covers the entire spectrum from the example with all three structural units (single chain, proto-fibril, super-fibril) exhibiting micelle-like form, through gradually emerging examples of local disorder, to structures with an extremely different structuring pattern. The water environment directing protein structures towards the generation of ribbon micelle-like structures (concentration of hydrophobic residues in the center of the molecule forming a hydrophobic core with the exposure of polar residues on the surface) also plays a role in the amyloid forms of α-synuclein. The polymorphic forms of α-synuclein reveal local structural differentiation with a common tendency to accept the micelle-like structuralization in certain common fragments of the polypeptide chain of this protein. Full article

(This article belongs to the Special Issue Amyloid Pathology: Cellular Mechanism and Therapy Targets)

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Review

Jump to: Research

15 pages, 615 KiB

Open AccessReview

The Roles of the Amyloid Beta Monomers in Physiological and Pathological Conditions

by Thomas Gabriel Schreiner, Oliver Daniel Schreiner, Maricel Adam and Bogdan Ovidiu Popescu

Biomedicines 2023, 11(5), 1411; https://doi.org/10.3390/biomedicines11051411 - 10 May 2023

Cited by 6 | Viewed by 2033

Abstract

Amyloid beta peptide is an important biomarker in Alzheimer’s disease, with the amyloidogenic hypothesis as one of the central hypotheses trying to explain this type of dementia. Despite numerous studies, the etiology of Alzheimer’s disease remains incompletely known, as the pathological accumulation of [...] Read more.

Amyloid beta peptide is an important biomarker in Alzheimer’s disease, with the amyloidogenic hypothesis as one of the central hypotheses trying to explain this type of dementia. Despite numerous studies, the etiology of Alzheimer’s disease remains incompletely known, as the pathological accumulation of amyloid beta aggregates cannot fully explain the complex clinical picture of the disease. Or, for the development of effective therapies, it is mandatory to understand the roles of amyloid beta at the brain level, from its initial monomeric stage prior to aggregation in the form of senile plaques. In this sense, this review aims to bring new, clinically relevant data on a subject intensely debated in the literature in the last years. In the first part, the amyloidogenic cascade is reviewed and the possible subtypes of amyloid beta are differentiated. In the second part, the roles played by the amyloid beta monomers in physiological and pathological (neurodegenerative) conditions are illustrated based on the most relevant and recent studies published on this topic. Finally, considering the importance of amyloid beta monomers in the pathophysiology of Alzheimer’s disease, new research directions with diagnostic and therapeutic impacts are suggested. Full article

(This article belongs to the Special Issue Amyloid Pathology: Cellular Mechanism and Therapy Targets)

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