Peptides, Peptidomimetics, and Carbohydrate–Peptide Conjugates as Amyloidogenic Aggregation Inhibitors for Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder accounting for 60-80% of dementia cases. For many years, AD causality was attributed to amyloid-β (Aβ) aggregated species. Recently, multiple therapies that target Aβ aggregation have failed in clinical trials, since Aβ aggregation is found in AD and healthy patients. Attention has therefore shifted toward the aggregation of the tau protein as a major driver of AD. Numerous inhibitors of tau-based pathology have recently been developed. Diagnosis of AD has shifted from measuring late stage senile plaques to early stage biomarkers, amyloid-β and tau monomers and oligomeric assemblies. Synthetic peptides and some derivative structures are being explored for use as theranostic tools as they possess the capacity both to bind the biomarkers and to inhibit their pathological self-assembly. Several studies have demonstrated that O-linked glycoside addition can significantly alter amyloid aggregation kinetics. Furthermore, natural O-glycosylation of amyloid-forming proteins, including amyloid precursor protein (APP), tau, and α-synuclein, promotes alternative nonamyloidogenic processing pathways. As such, glycopeptides and related peptidomimetics are being investigated within the AD field. Here we review advancements made in the last 5 years, as well as the arrival of sugar-based derivatives.

The tetrameric peptide LfcinB (20–25)4 derived from bovine lactoferricin induces apoptosis in the MCF-7 breast cancer cell line

“…Antimicrobial peptides (AMPs) are a promising alternative, due to their ability to establish different points of contact with their target and selective interactions that will generate a decrease in side effects. 6 AMPs are part of the innate immune system and exhibit a cytotoxic effect against bacteria and cancer cells, and are a viable alternative for identifying promising molecules for developing new therapeutic agents. 7,8 AMPs are able to discriminate between cancer and non-cancer cells due to electrostatic interactions between positively-charged amino acids and the negatively-charged membrane components such as phosphatidylserine, glycosylated mucins, sialylated gangliosides, sialic acid, and heparan sulphate.…”

Modulation of aggregation with an electric field; scientific roadmap for a potential non-invasive therapy against tauopathies

“…1 Although this number is expected to increase to 132 million by 2050, there is no clinically approved therapy to cure or retard its progression. 1 Promising therapeutic strategies under research include native state stabilisation or brillation inhibition using small molecules, 2-6 immunotherapy, 7,8 peptide or peptidomimetics, [9][10][11][12][13][14][15][16][17][18] nanoparticles, 19,20 transient metals, [21][22][23][24] supramolecular inhibition of brillation 25,26 and sequestering the monomeric form of the peptide. 27 Nucleation-dependent aggregation is one of the most accepted models for the formation of amyloid brils.…”

Long Non-coding RNAs in Peripheral Blood Mononuclear Cells Associated with Alzheimer Disease

“…For example, lncRNA known as BACE1-AS, has been shown to up-regulate in AD by affecting the stabilization of BACE1 mRNA and contribute to disease-specific amyloid beta 42 (A-42) protein formation (Akkaya and Dinçer 2013). Alzheimer's disease (AD) is the most common neurodegenerative disease and accounts for 60-80% of all dementia cases (Ryan et al 2018). Histopathologically, AD composed of plaques of amyloid beta (A) peptides are characterized by neurofibrillary tangles formed by hyperphosphorylated tau protein forms, as well as neuronal loss in specific regions of the brain (Prendecki et al 2019).…”