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Mol. Life Sci."],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) is characterized by progressive cognitive decline due to accumulating synaptic insults by toxic oligomers of amyloid beta (A\u03b2O) and tau (TauO). There is growing consensus that preventing these oligomers from interacting with synapses might be an effective approach to treat AD. However, recent clinical trial failures suggest low effectiveness of targeting A\u03b2 in late-stage AD. Researchers have redirected their attention toward TauO as the levels of this species increase later in disease pathogenesis. Here we show that A\u03b2O and TauO differentially target synapses and affect each other's binding dynamics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Binding of labeled, pre-formed A\u03b2 and tau oligomers onto synaptosomes isolated from the hippocampus and frontal cortex of mouse and\n                      <jats:italic>postmortem<\/jats:italic>\n                      cognitively intact elderly human brains was evaluated using flow-cytometry and western blot analyses. Binding of labeled, pre-formed A\u03b2 and tau oligomers onto mouse primary neurons was assessed using immunofluorescence assay. The synaptic dysfunction was measured by fluorescence analysis of single-synapse long-term potentiation (FASS-LTP) assay.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We demonstrated that higher TauO concentrations effectively outcompete A\u03b2O and become the prevailing synaptic-associated species. Conversely, high concentrations of A\u03b2O facilitate synaptic TauO recruitment. Immunofluorescence analyses of mouse primary cortical neurons confirmed differential synaptic binding dynamics of A\u03b2O and TauO. Moreover, in vivo experiments using old 3xTgAD mice ICV injected with either A\u03b2O or TauO fully supported these findings. Consistent with these observations, FASS-LTP analyses demonstrated that TauO-induced suppression of chemical LTP was exacerbated by A\u03b2O. Finally, predigestion with proteinase K abolished the ability of TauO to compete off A\u03b2O without affecting the ability of high A\u03b2O levels to increase synaptic TauO recruitment. Thus, unlike A\u03b2O, TauO effects on synaptosomes are hampered by the absence of protein substrate in the membrane.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results introduce the concept that TauO become the main synaptotoxic species at late AD, thus supporting the hypothesis that TauO may be the most effective therapeutic target for clinically manifest AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00018-022-04255-9","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T10:02:44Z","timestamp":1649066564000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["A\u03b2\/tau oligomer interplay at human synapses supports shifting therapeutic targets for Alzheimer\u2019s disease"],"prefix":"10.1007","volume":"79","author":[{"given":"Michela","family":"Marcatti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Fracassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Montalbano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandramouli","family":"Natarajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balaji","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakez","family":"Kayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4795-447X","authenticated-orcid":false,"given":"Giulio","family":"Taglialatela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,4]]},"reference":[{"issue":"July","key":"4255_CR1","first-page":"1","volume":"13","author":"C Fabiani","year":"2019","unstructured":"Fabiani C, Antollini SS (2019) Alzheimer\u2019s disease as a membrane disorder: Spatial cross-talk among beta-amyloid peptides, nicotinic acetylcholine receptors and lipid rafts. 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