Abstract
So far, there is no effective disease-modifying therapies for Alzheimer’s Disease (AD) in clinical practice. In this context, glycine-L-proline-L-glutamate (GPE) and its analogs may open the way for developing a novel molecule for treating neurodegenerative disorders, including AD. In turn, this study was aimed to investigate the neuroprotective potentials exerted by three novel GPE peptidomimetics (GPE1, GPE2, and GPE3) using an in vitro AD model. Anti-Alzheimer potentials were determined using a wide array of techniques, such as measurements of mitochondrial viability (MTT) and lactate dehydrogenase (LDH) release assays, determination of acetylcholinesterase (AChE), α-secretase and β-secretase activities, comparisons of total antioxidant capacity (TAC) and total oxidative status (TOS) levels, flow cytometric and microscopic detection of apoptotic and necrotic neuronal death, and investigating gene expression responses via PCR arrays involving 64 critical genes related to 10 different pathways. Our analysis showed that GPE peptidomimetics modulate oxidative stress, ACh depletion, α-secretase inactivation, apoptotic, and necrotic cell death. In vitro results suggested that treatments with novel GPE analogs might be promising therapeutic agents for treatment and/or or prevention of AD.
Highlights
SH-SY5Y human neuroblastoma cells’ differentiation process to neuronal-like cells included using a combination of RA and BDNF
SH-SY5Y cells compared to undifferentiated cell cultures (Figure 2)
To choose the most appropriate Aβ1-42 concentration for anti-Alzheimer’s Disease (AD) assessments, a wide range of Aβ concentrations involving 1.25, 2.5, 5, 10, 20, 40, 80, 160, and 320 μM were applied into the cellular model for 24 h (n = 6)
Summary
The glycine-L-proline-L-glutamate (GPE) (Figure 1) is a naturally cleaved N-terminal tripeptide of IGF-1 via brain proteases. It is commercially available as Glypromate [1,2]. GPE executes remarkable neuroprotective properties in several in vitro and in vivo models, demonstrating its involvement in traumatic brain injury and chronic neurodegeneration [3,4,5,6,7,8,9]
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