Neuroepigenetic Mechanisms of Action of Ultrashort Peptides in Alzheimer's Disease

Abstract

Epigenetic regulation of gene expression is necessary for maintaining higher-order cognitive functions (learning and memory). The current understanding of the role of epigenetics in the mechanism of Alzheimer's disease (AD) is focused on DNA methylation, chromatin remodeling, histone modifications, and regulation of non-coding RNAs. The pathogenetic links of this disease are the misfolding and aggregation of tau protein and amyloid peptides, mitochondrial dysfunction, oxidative stress, impaired energy metabolism, destruction of the blood-brain barrier, and neuroinflammation, all of which lead to impaired synaptic plasticity and memory loss. Ultrashort peptides are promising neuroprotective compounds with a broad spectrum of activity and without reported side effects. The main aim of this review is to analyze the possible epigenetic mechanisms of the neuroprotective action of ultrashort peptides in AD. The review highlights the role of short peptides in the AD pathophysiology. We formulate the hypothesis that peptide regulation of gene expression can be mediated by the interaction of short peptides with histone proteins, cis- and transregulatory DNA elements and effector molecules (DNA/RNA-binding proteins and non-coding RNA). The development of therapeutic agents based on ultrashort peptides may offer a promising addition to the multifunctional treatment of AD.

Keywords: Alzheimer’s disease; DNA; DNA-binding proteins; histones; neuroepigenetic; non-coding RNA; nucleosome; promotors; transcription factors; ultrashort peptides.

Figure 1

Potential neuroprotective roles of ultrashort peptides (KE, EDR, KED, AEDG, KEDW, and MEHFPGP) in AD. Note: BBB—blood–brain barrier, ROS—reactive oxygen species. (figure created with BioRender.com, accessed on 25 February 2022)

Figure 2

Potential epigenetic mechanisms of gene expression regulation by using ultrashort peptides. The levels of regulation: I—chromatin level, II—interference of peptides with DNA Methylation/Demethylation, III—interaction of short peptides with cis-regulatory elements of the genome and transcription factors, IV—RNA level. Note: DNMTs—DNA methyl- transferases, Me—methylation, TF—transcription factors, TETs—translocation enzymes. (figure created with BioRender.com, accessed on 25 February 2022)

Figure 3

Site-specific binding of peptides EW (a), KE (b), EDR (c), AEDG (d), and KEDW (e) to double-stranded DNA in the classical B-form. Note: ICM-Score—the Internal Coordinate Mechanics binding score. Standard scheme of atom designation was following: C—yellow (green), N—blue, O—red.

Figure 4

Functional relationship of proteins encoded by AD-associated genes according to the PathCards database [144]. Proportion of proteins in functional clusters (left). Protein–protein interaction networks (right).

Figure 5

Functional relationship of proteins encoded by AD-associated genes—potential targets of the EW peptide (specific targets for EW peptide are marked with a red circle). Proportion of proteins in functional clusters (left). Protein–protein interaction networks (right): solid line shows the relationships between proteins within the same cluster, and dotted line shows the relationships between clusters.

Figure 6

Functional relationship of proteins encoded by AD-associated genes—potential targets of the KE peptide (specific targets for KE peptide are marked with a red circle). Proportion of proteins in functional clusters (left). Protein–protein interaction networks (right): solid line shows the relationships between proteins within the same cluster, and dotted line shows the relationships between clusters.

Figure 7

Functional relationship of proteins encoded by AD-associated genes—potential targets of the EDR peptide (specific targets for EDR peptide are marked with a red circle). Proportion of proteins in functional clusters (left). Protein–protein interaction networks (right): solid line shows the relationships between proteins within the same cluster, and dotted line shows the relationships between clusters.

Figure 8

Role of miRNAs in the pathophysiology of AD. (figure created with BioRender.com, accessed on 25 February 2022)

Figure 9

Concept of peptide regulation of neurodegenerative processes in Alzheimer’s disease. Note: BBB—blood–brain barrier. (figure created with BioRender.com, accessed on 25 February 2022)