Physiological expression of mutated TAU impaired astrocyte activity and exacerbates β-amyloid pathology in 5xFAD mice
Abstract Background Alzheimer’s disease (AD) is the leading cause of dementia in the world. The pathology of AD is affiliated with the elevation of both tau (τ) and β-amyloid (Aβ) pathologies. Yet, the direct link between natural τ expression on glia cell activity and Aβ remains unclear. While exper...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-07-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02823-9 |
| _version_ | 1827890293031043072 |
|---|---|
| author | Dorit Farfara Meital Sooliman Limor Avrahami Tabitha Grace Royal Shoshik Amram Lea Rozenstein-Tsalkovich Dorit Trudler Shani Blanga-Kanfi Hagit Eldar-Finkelman Jens Pahnke Hanna Rosenmann Dan Frenkel |
| author_facet | Dorit Farfara Meital Sooliman Limor Avrahami Tabitha Grace Royal Shoshik Amram Lea Rozenstein-Tsalkovich Dorit Trudler Shani Blanga-Kanfi Hagit Eldar-Finkelman Jens Pahnke Hanna Rosenmann Dan Frenkel |
| author_sort | Dorit Farfara |
| collection | DOAJ |
| description | Abstract Background Alzheimer’s disease (AD) is the leading cause of dementia in the world. The pathology of AD is affiliated with the elevation of both tau (τ) and β-amyloid (Aβ) pathologies. Yet, the direct link between natural τ expression on glia cell activity and Aβ remains unclear. While experiments in mouse models suggest that an increase in Aβ exacerbates τ pathology when expressed under a neuronal promoter, brain pathology from AD patients suggests an appearance of τ pathology in regions without Aβ. Methods Here, we aimed to assess the link between τ and Aβ using a new mouse model that was generated by crossing a mouse model that expresses two human mutations of the human MAPT under a mouse Tau natural promoter with 5xFAD mice that express human mutated APP and PS1 in neurons. Results The new mouse model, called 5xFAD TAU, shows accelerated cognitive impairment at 2 months of age, increased number of Aβ depositions at 4 months and neuritic plaques at 6 months of age. An expression of human mutated TAU in astrocytes leads to a dystrophic appearance and reduces their ability to engulf Aβ, which leads to an increased brain Aβ load. Astrocytes expressing mutated human TAU showed an impairment in the expression of vascular endothelial growth factor (VEGF) that has previously been suggested to play an important role in supporting neurons. Conclusions Our results suggest the role of τ in exacerbating Aβ pathology in addition to pointing out the potential role of astrocytes in disease progression. Further research of the crosstalk between τ and Aβ in astrocytes may increase our understanding of the role glia cells have in the pathology of AD with the aim of identifying novel therapeutic interventions to an otherwise currently incurable disease. |
| first_indexed | 2024-03-12T21:07:50Z |
| format | Article |
| id | doaj.art-36f940c1cd774042b9dbd3ca9047e489 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-12T21:07:50Z |
| publishDate | 2023-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-36f940c1cd774042b9dbd3ca9047e4892023-07-30T11:21:04ZengBMCJournal of Neuroinflammation1742-20942023-07-0120111510.1186/s12974-023-02823-9Physiological expression of mutated TAU impaired astrocyte activity and exacerbates β-amyloid pathology in 5xFAD miceDorit Farfara0Meital Sooliman1Limor Avrahami2Tabitha Grace Royal3Shoshik Amram4Lea Rozenstein-Tsalkovich5Dorit Trudler6Shani Blanga-Kanfi7Hagit Eldar-Finkelman8Jens Pahnke9Hanna Rosenmann10Dan Frenkel11Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv UniversityDepartment of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv UniversityDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, George S. Wise Faculty of Life Sciences, Tel Aviv UniversityDepartment of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv UniversityDepartment of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv UniversityDepartment of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical CenterDepartment of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv UniversityDepartment of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv UniversityDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, George S. Wise Faculty of Life Sciences, Tel Aviv UniversityDepartment of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv UniversityDepartment of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical CenterDepartment of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv UniversityAbstract Background Alzheimer’s disease (AD) is the leading cause of dementia in the world. The pathology of AD is affiliated with the elevation of both tau (τ) and β-amyloid (Aβ) pathologies. Yet, the direct link between natural τ expression on glia cell activity and Aβ remains unclear. While experiments in mouse models suggest that an increase in Aβ exacerbates τ pathology when expressed under a neuronal promoter, brain pathology from AD patients suggests an appearance of τ pathology in regions without Aβ. Methods Here, we aimed to assess the link between τ and Aβ using a new mouse model that was generated by crossing a mouse model that expresses two human mutations of the human MAPT under a mouse Tau natural promoter with 5xFAD mice that express human mutated APP and PS1 in neurons. Results The new mouse model, called 5xFAD TAU, shows accelerated cognitive impairment at 2 months of age, increased number of Aβ depositions at 4 months and neuritic plaques at 6 months of age. An expression of human mutated TAU in astrocytes leads to a dystrophic appearance and reduces their ability to engulf Aβ, which leads to an increased brain Aβ load. Astrocytes expressing mutated human TAU showed an impairment in the expression of vascular endothelial growth factor (VEGF) that has previously been suggested to play an important role in supporting neurons. Conclusions Our results suggest the role of τ in exacerbating Aβ pathology in addition to pointing out the potential role of astrocytes in disease progression. Further research of the crosstalk between τ and Aβ in astrocytes may increase our understanding of the role glia cells have in the pathology of AD with the aim of identifying novel therapeutic interventions to an otherwise currently incurable disease.https://doi.org/10.1186/s12974-023-02823-9TauBeta-amyloid5xFADMouse modelAstrocytesAlzheimer’s disease |
| spellingShingle | Dorit Farfara Meital Sooliman Limor Avrahami Tabitha Grace Royal Shoshik Amram Lea Rozenstein-Tsalkovich Dorit Trudler Shani Blanga-Kanfi Hagit Eldar-Finkelman Jens Pahnke Hanna Rosenmann Dan Frenkel Physiological expression of mutated TAU impaired astrocyte activity and exacerbates β-amyloid pathology in 5xFAD mice Journal of Neuroinflammation Tau Beta-amyloid 5xFAD Mouse model Astrocytes Alzheimer’s disease |
| title | Physiological expression of mutated TAU impaired astrocyte activity and exacerbates β-amyloid pathology in 5xFAD mice |
| title_full | Physiological expression of mutated TAU impaired astrocyte activity and exacerbates β-amyloid pathology in 5xFAD mice |
| title_fullStr | Physiological expression of mutated TAU impaired astrocyte activity and exacerbates β-amyloid pathology in 5xFAD mice |
| title_full_unstemmed | Physiological expression of mutated TAU impaired astrocyte activity and exacerbates β-amyloid pathology in 5xFAD mice |
| title_short | Physiological expression of mutated TAU impaired astrocyte activity and exacerbates β-amyloid pathology in 5xFAD mice |
| title_sort | physiological expression of mutated tau impaired astrocyte activity and exacerbates β amyloid pathology in 5xfad mice |
| topic | Tau Beta-amyloid 5xFAD Mouse model Astrocytes Alzheimer’s disease |
| url | https://doi.org/10.1186/s12974-023-02823-9 |
| work_keys_str_mv | AT doritfarfara physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT meitalsooliman physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT limoravrahami physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT tabithagraceroyal physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT shoshikamram physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT learozensteintsalkovich physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT dorittrudler physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT shaniblangakanfi physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT hagiteldarfinkelman physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT jenspahnke physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT hannarosenmann physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice AT danfrenkel physiologicalexpressionofmutatedtauimpairedastrocyteactivityandexacerbatesbamyloidpathologyin5xfadmice |