{"id":639,"date":"2018-10-13T15:43:10","date_gmt":"2018-10-13T06:43:10","guid":{"rendered":"http:\/\/www.neuroscienceres.com\/?p=639"},"modified":"2022-01-07T10:04:57","modified_gmt":"2022-01-07T03:04:57","slug":"vivo-aav-based-models-firmly-support-unifying-hypothesis","status":"publish","type":"post","link":"http:\/\/www.neuroscienceres.com\/index.php\/2018\/10\/13\/vivo-aav-based-models-firmly-support-unifying-hypothesis\/","title":{"rendered":"The in vivo AAV-based models firmly support the unifying hypothesis"},"content":{"rendered":"

In an experimental model, absence of protein tau alleviated the cognitive defects inflicted by amyloid,Z-VAD-FMK<\/a> while expressing human wild-type tau causes no or minimal tauopathy. Conversely, mice expressing mutant tau associated with familial fronto-temporal dementia recapitulate robust tauopathy. Bigenic and multiple transgenic mice expressing various combinations of mutant APP and mutant tau recapitulate the combined amyloid and tau-pathology of AD, but lack neurodegeneration and brain-atrophy typical for AD. Here we expressed Tau or APP, both wild-type and mutants, by adeno-associated viral vectors injected directly into the hippocampus of wild-type mice. The observed dramatic pyramidal neuro-degeneration inflicted by wild-type Tau4R and by mutant Tau-P301L within weeks,Regorafenib<\/a> contrasted with mutant APP that provoked amyloid pathology after 6 months but with only minor neurodegeneration. Importantly, tau-mediated neurodegeneration was not caused by fibrillar tau-aggregates. Most prominent were cell-cycle markers, indicating that degenerating neurons were attempting to re-entry the cell-cycle. The in vivo AAV-based models firmly support the unifying hypothesis that protein tau mediates neurodegeneration by forcing post-mitotic neurons to re-enter the cell-cycle in primary and secondary tauopathies. Initial experiments were performed with triple mutant APP.-SLA, described in the next paragraph, and mutant Tau.P301L, both packaged in AAV-vectors with hybrid serotype-1\/2. Intracerebral injection of these vectors into the hippocampal complex of wild-type mice, expresses the embedded cDNA under control of the human synapsin-1 promoter, specifically in pyramidal neurons of hippocampus and cortex. The generated triple mutant APP.SLA construct contained the Swedish, London and Austrian mutations that are associated with early-onset familial AD. Transient expression in neuro-blastoma cells demonstrated APP.SLA to produce highest levels of Ab42. Tau.P301L is associated with FTDP-17 and produced experimentally robust tauopathy in single and bigenic mice by us and others. Initially, brains were analyzed 12 weeks after intracerebral injection of AAV-vectors in wild-type mice. <\/p>\n","protected":false},"excerpt":{"rendered":"

In an experimental model, absence of protein tau alleviated the cognitive defects inflicted by amyloid,Z-VAD-FMK while expressing human wild-type tau causes no or minimal tauopathy. Conversely, mice expressing mutant tau associated with familial fronto-temporal dementia recapitulate robust tauopathy. Bigenic and multiple transgenic mice expressing various combinations of mutant APP and mutant tau recapitulate the combined … Continue reading The in vivo AAV-based models firmly support the unifying hypothesis<\/span><\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[1],"tags":[],"_links":{"self":[{"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/posts\/639"}],"collection":[{"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/comments?post=639"}],"version-history":[{"count":1,"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/posts\/639\/revisions"}],"predecessor-version":[{"id":640,"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/posts\/639\/revisions\/640"}],"wp:attachment":[{"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/media?parent=639"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/categories?post=639"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/www.neuroscienceres.com\/index.php\/wp-json\/wp\/v2\/tags?post=639"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}