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Soluble oligomers are the most synaptotoxic forms of amyloid \u00df-protein (A\u00df) and mediate synaptic plasticity disruption in Alzheimer\u2019s disease amyloidosis. Because the presence and extent of cortisol excess in prodromal Alzheimer\u2019s disease predicts the onset of cognitive symptoms we hypothesised that corticosteroids would exacerbate the inhibition of hippocampal synaptic long-term potentiation in a rat model of Alzheimer\u2019s disease amyloidosis. In a longitudinal experimental design using freely behaving pre-plaque McGill-R-Thy1-APP male rats, three injections of corticosterone or the glucocorticoid methylprednisolone profoundly disrupted long-term potentiation induced by strong conditioning stimulation for at least 2 months. The same treatments had a transient or no detectible detrimental effect on synaptic plasticity in wild-type littermates. Moreover, corticosterone-mediated cognitive dysfunction, as assessed in a novel object recognition test, was more persistent in the transgenic animals. Evidence for the involvement of pro-inflammatory mechanisms was provided by the ability of the selective the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome inhibitor Mcc950 to reverse the synaptic plasticity deficit in corticosterone-treated transgenic animals. The marked prolongation of the synaptic plasticity disrupting effects of brief corticosteroid excess substantiates a causal role for hypothalamic-pituitary-adrenal axis dysregulation in early Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1038\/s41386-021-01056-9","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T08:02:48Z","timestamp":1624953768000},"page":"2170-2179","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Enduring glucocorticoid-evoked exacerbation of synaptic plasticity disruption in male rats modelling early Alzheimer\u2019s disease amyloidosis"],"prefix":"10.1038","volume":"46","author":[{"given":"Yingjie","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Klyubin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Ondrejcak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neng-Wei","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Rowan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,29]]},"reference":[{"key":"1056_CR1","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1210\/edrv-7-3-284","volume":"7","author":"RM Sapolsky","year":"1986","unstructured":"Sapolsky RM, Krey LC, McEwen BS. 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