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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\u03b2 (5 and 10\u00a0\u03bcM) 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\u00a0(ROS) and lactate dehydrogenase (LDH) as well as reduced cell viability. Following 24\u00a0h of exposure, PaPE-1 inhibited A\u03b2-evoked effects, as shown by reduced parameters of neurotoxicity, oxidative stress, and apoptosis. Because PaPE-1 downregulated A\u03b2-induced <jats:italic>Fas<\/jats:italic>\/FAS expression but upregulated that of A\u03b2-induced <jats:italic>FasL<\/jats:italic>, the role of PaPE-1 in controlling the external apoptotic pathway is controversial. However, PaPE-1 normalized A\u03b2-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.<\/jats:p>","DOI":"10.1007\/s12640-020-00289-8","type":"journal-article","created":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T01:03:11Z","timestamp":1602032591000},"page":"957-966","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Selective Targeting of Non-nuclear Estrogen Receptors with PaPE-1 as a New Treatment Strategy for Alzheimer\u2019s Disease"],"prefix":"10.1007","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3620-3902","authenticated-orcid":false,"given":"Agnieszka","family":"Wnuk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Przepi\u00f3rska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Rzemieniec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadeta","family":"Pietrzak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Kajta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,6]]},"reference":[{"issue":"2","key":"289_CR1","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1152\/physrev.00023.2009","volume":"90","author":"B De Strooper","year":"2010","unstructured":"De Strooper B (2010) Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. 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