Journal Article

Posttreatment with PaPE-1 Protects from Aβ-Induced Neurodegeneration Through Inhibiting the Expression of Alzheimer’s Disease-Related Genes and Apoptosis Process That Involves Enhanced DNA Methylation of Specific Genes

Łach, Andrzej, Kajta, Małgorzata, Wnuk, Agnieszka, Pietrzak-Wawrzyńska, Bernadeta A., Przepiórska-Drońska, Karolina

2024

Overview

Targeting the non-nuclear estrogen receptor (ER) signaling has been postulated as novel therapeutic strategy for central nervous system pathologies. Recently, we showed that newly designed PaPE-1 (Pathway Preferential Estrogen-1), which selectively activates ER non-nuclear signaling pathways, elicited neuroprotection in a cellular model of Alzheimer’s disease (AD) when it was applied at the same time as amyloid-β (Aβ). Since delayed treatment reflects clinical settings better than cotreatment does, current basic study proposes a novel therapeutic approach for AD that relies on a posttreatment with PaPE-1. In this study, mouse neuronal cell cultures treated with preaggregated Aβ 1-42 (10 µM) showed the presence of extracellular Aβ 1-42 , confirming the adequacy of the AD model used. We are the first to demonstrate that a 24-h delayed posttreatment with PaPE-1 decreased the degree of Aβ-induced neurodegeneration, restored neurite outgrowth, and inhibited the expression of AD-related genes, i.e., Rbfox , Apoe , Bace2 , App , and Ngrn , except for Chat , which was stimulated. In addition, PaPE-1 elicited anti-apoptotic effects by inhibiting Aβ-induced caspase activities as well as attenuating apoptotic chromatin condensation, and in these ways, PaPE-1 prevented neuronal cell death. Posttreatment with PaPE-1 also downregulated the Aβ-affected mRNA expression of apoptosis-specific factors, such as Bax , Gsk3b , Fas , and Fasl , except for Bcl2 , which was upregulated by PaPE-1. In parallel, PaPE-1 decreased the protein levels of BAX, FAS, and FASL, which were elevated in response to Aβ. PaPE-1 elicited a decrease in the BAX/BCL2 ratio that corresponds to increased methylation of the Bax gene. However, the PaPE-1-evoked Bcl2 gene hypermethylation suggests other PaPE-1-dependent mechanisms to control Aβ-induced apoptosis.

• Publisher: Springer US,Springer Nature B.V
• Subject: Alzheimer Disease - genetics / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid beta-Peptides - toxicity / Animals / Apolipoprotein E / Apoptosis / Apoptosis - drug effects / Axonogenesis / BAX gene / BAX protein / Bcl-2 protein / Biomedical and Life Sciences / Biomedicine / Caspase / Cell Biology / Cell death / Central nervous system / Chromatin / DNA methylation / DNA Methylation - drug effects / DNA Methylation - genetics / Down-regulation / Estrogen receptors / Estrogens / FasL protein / Gene expression / Gene Expression Regulation - drug effects / Genes / Mice / Nerve Degeneration - genetics / Nerve Degeneration - pathology / Neurobiology / Neurodegeneration / Neurodegenerative diseases / Neurology / Neurons - drug effects / Neurons - metabolism / Neurons - pathology / Neuroprotection / Neuroprotective Agents - pharmacology / Neurosciences / Signal transduction / β-Amyloid / β-Site APP-cleaving enzyme 2