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ApoER2-Dab1 signaling suppresses Tau phosphorylation as part of a four-arm pathway that regulates lipoprotein internalization and the integrity of actin, microtubules, and synapses; however, the role of this pathway in sAD pathogenesis is not fully understood. We previously showed that multiple ApoER2-Dab1 pathway components including ApoE, Reelin, ApoER2, Dab1, pP85\u03b1<jats:sub>Tyr607<\/jats:sub>, pLIMK1<jats:sub>Thr508<\/jats:sub>, pTau<jats:sub>Ser202\/Thr205<\/jats:sub> and pPSD95<jats:sub>Thr19<\/jats:sub> accumulate together within entorhinal-hippocampal terminal zones in sAD, and proposed a unifying hypothesis wherein disruption of this pathway underlies multiple aspects of sAD pathogenesis. However, it is not yet known whether ApoER2-Dab1 disruption can help explain the origin(s) and early progression of pTau pathology in sAD. In the present study, we applied in situ hybridization and immunohistochemistry (IHC) to characterize ApoER2 expression and accumulation of ApoER2-Dab1 pathway components in five regions known to develop early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD. We found that (1) these selectively vulnerable neuron populations strongly express ApoER2; and (2) multiple ApoER2-Dab1 components representing all four arms of this pathway accumulate in abnormal neurons and neuritic plaques in mild cognitive impairment (MCI) and sAD cases and correlate with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85\u03b1<jats:sub>Tyr607<\/jats:sub>, pLIMK1<jats:sub>Thr508<\/jats:sub>, pTau<jats:sub>Ser202\/Thr205<\/jats:sub> and pPSD95<jats:sub>Thr19<\/jats:sub> accumulate together within many of the same ApoER2-expressing neurons and in the immediate vicinity of ApoE\/ApoJ-enriched extracellular plaques. Collective findings reveal that pTau is only one of many ApoER2-Dab1 pathway components that accumulate in multiple neuroanatomical sites in the earliest stages of sAD and provide support for the concept that ApoER2-Dab1 disruption drives pTau-associated neurodegeneration in human sAD.<\/jats:p>","DOI":"10.1186\/s40478-023-01693-9","type":"journal-article","created":{"date-parts":[[2023,12,13]],"date-time":"2023-12-13T13:02:24Z","timestamp":1702472544000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4058-7630","authenticated-orcid":false,"given":"Christopher E.","family":"Ramsden","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisy","family":"Zamora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Horowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jahandar","family":"Jahanipour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Calzada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory S.","family":"Keyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen C.","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice A.","family":"Curtis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Faull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Sedlock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dragan","family":"Maric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,12,13]]},"reference":[{"key":"1693_CR1","doi-asserted-by":"publisher","first-page":"2195","DOI":"10.1002\/cne.23270","volume":"521","author":"KL Agster","year":"2013","unstructured":"Agster KL, Mejias-Aponte CA, Clark BD, Waterhouse BD (2013) Evidence for a regional specificity in the density and distribution of noradrenergic varicosities in rat cortex. 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