ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease
Abstract In sporadic Alzheimer’s disease (sAD) specific regions, layers and neurons accumulate hyperphosphorylated Tau (pTau) and degenerate early while others remain unaffected even in advanced disease. ApoER2-Dab1 signaling suppresses Tau phosphorylation as part of a four-arm pathway that regulate...
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| Format: | Article |
| Language: | English |
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BMC
2023-12-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40478-023-01693-9 |
| _version_ | 1827581325628932096 |
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| author | Christopher E. Ramsden Daisy Zamora Mark S. Horowitz Jahandar Jahanipour Elizabeth Calzada Xiufeng Li Gregory S. Keyes Helen C. Murray Maurice A. Curtis Richard M. Faull Andrea Sedlock Dragan Maric |
| author_facet | Christopher E. Ramsden Daisy Zamora Mark S. Horowitz Jahandar Jahanipour Elizabeth Calzada Xiufeng Li Gregory S. Keyes Helen C. Murray Maurice A. Curtis Richard M. Faull Andrea Sedlock Dragan Maric |
| author_sort | Christopher E. Ramsden |
| collection | DOAJ |
| description | Abstract In sporadic Alzheimer’s disease (sAD) specific regions, layers and neurons accumulate hyperphosphorylated Tau (pTau) and degenerate early while others remain unaffected even in advanced disease. 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, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 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, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 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. |
| first_indexed | 2024-03-08T22:34:46Z |
| format | Article |
| id | doaj.art-e3736605578a4ed187f90e071e5def20 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-03-08T22:34:46Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-e3736605578a4ed187f90e071e5def202023-12-17T12:33:13ZengBMCActa Neuropathologica Communications2051-59602023-12-0111113110.1186/s40478-023-01693-9ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s diseaseChristopher E. Ramsden0Daisy Zamora1Mark S. Horowitz2Jahandar Jahanipour3Elizabeth Calzada4Xiufeng Li5Gregory S. Keyes6Helen C. Murray7Maurice A. Curtis8Richard M. Faull9Andrea Sedlock10Dragan Maric11Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH (NIA/NIH)Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH (NIA/NIH)Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH (NIA/NIH)Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, NIHLipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH (NIA/NIH)Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH (NIA/NIH)Lipid Peroxidation Unit, Laboratory of Clinical Investigation, National Institute on Aging, NIH (NIA/NIH)Department of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of AucklandDepartment of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of AucklandDepartment of Anatomy and Medical Imaging and Centre for Brain Research, Faculty of Medical and Health Science, University of AucklandFlow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, NIHFlow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, NIHAbstract In sporadic Alzheimer’s disease (sAD) specific regions, layers and neurons accumulate hyperphosphorylated Tau (pTau) and degenerate early while others remain unaffected even in advanced disease. 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, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 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, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 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.https://doi.org/10.1186/s40478-023-01693-9ApoER2ApoEDab1Alzheimer's diseaseP85αLIMK1 |
| spellingShingle | Christopher E. Ramsden Daisy Zamora Mark S. Horowitz Jahandar Jahanipour Elizabeth Calzada Xiufeng Li Gregory S. Keyes Helen C. Murray Maurice A. Curtis Richard M. Faull Andrea Sedlock Dragan Maric ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease Acta Neuropathologica Communications ApoER2 ApoE Dab1 Alzheimer's disease P85α LIMK1 |
| title | ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease |
| title_full | ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease |
| title_fullStr | ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease |
| title_full_unstemmed | ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease |
| title_short | ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer’s disease |
| title_sort | apoer2 dab1 disruption as the origin of ptau associated neurodegeneration in sporadic alzheimer s disease |
| topic | ApoER2 ApoE Dab1 Alzheimer's disease P85α LIMK1 |
| url | https://doi.org/10.1186/s40478-023-01693-9 |
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