Journal
NEUROTOXICITY RESEARCH
Volume 38, Issue 4, Pages 957-966Publisher
SPRINGER
DOI: 10.1007/s12640-020-00289-8
Keywords
Alzheimer's disease; Neurodegeneration; Neuroprotection; Estrogen receptors; Non-nuclear ERs
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Funding
- Maj Institute of Pharmacology, PolishAcademy of Sciences inKrakow, Poland
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Alzheimer's disease (AD) is a multifactorial and severe neurodegenerative disorder characterized by progressive memory decline, the presence of A beta plaques and tau tangles, brain atrophy, and neuronal loss. Available therapies provide moderate symptomatic relief but do not alter disease progression. This study demonstrated that PaPE-1, which has been designed to selectively activate non-nuclear estrogen receptors (ERs), has anti-AD capacity, as evidenced in a cellular model of the disease. In this model, the treatment of mouse neocortical neurons with A beta (5 and 10 mu M) induced apoptosis (loss of mitochondrial membrane potential, activation of caspase-3, induction of apoptosis-related genes and proteins) accompanied by increases in levels of reactive oxygen species (ROS) and lactate dehydrogenase (LDH) as well as reduced cell viability. Following 24 h of exposure, PaPE-1 inhibited A beta-evoked effects, as shown by reduced parameters of neurotoxicity, oxidative stress, and apoptosis. Because PaPE-1 downregulated A beta-inducedFas/FAS expression but upregulated that of A beta-inducedFasL, the role of PaPE-1 in controlling the external apoptotic pathway is controversial. However, PaPE-1 normalized A beta-induced loss of mitochondrial membrane potential and restored the BAX/BCL2 ratio, suggesting that the anti-AD capacity of PaPE-1 particularly relies on inhibition of the mitochondrial apoptotic pathway. These data provide new evidence for an anti-AD strategy that utilizes the selective targeting of non-nuclear ERs with PaPE-1.
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