A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3
Abstract Background Alzheimer’s disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aβ). APOE is the greatest genetic risk for AD with APOE4 increasing risk up to ~ 15-fold compared to APOE3. Evidence suggests that levels and lipidation of...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-12-01
|
| Series: | Alzheimer’s Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13195-023-01353-z |
| _version_ | 1797388512899629056 |
|---|---|
| author | Ana C. Valencia-Olvera Deebika Balu Shreya Bellur Thomas McNally Yaseen Saleh Don Pham Shivesh Ghura Jason York Jan O. Johansson Mary Jo LaDu Leon Tai |
| author_facet | Ana C. Valencia-Olvera Deebika Balu Shreya Bellur Thomas McNally Yaseen Saleh Don Pham Shivesh Ghura Jason York Jan O. Johansson Mary Jo LaDu Leon Tai |
| author_sort | Ana C. Valencia-Olvera |
| collection | DOAJ |
| description | Abstract Background Alzheimer’s disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aβ). APOE is the greatest genetic risk for AD with APOE4 increasing risk up to ~ 15-fold compared to APOE3. Evidence suggests that levels and lipidation of the apoE protein could regulate AD progression. In glia, apoE is lipidated via cholesterol efflux from intracellular pools, primarily by the ATP-binding cassette transporter A1 (ABCA1). Therefore, increasing ABCA1 activity is suggested to be a therapeutic approach for AD. CS-6253 (CS) is a novel apoE mimetic peptide that was developed to bind and stabilize ABCA1 and maintain its localization into the plasma membrane therefore promoting cholesterol efflux. The goal of this study was to determine whether CS could modulate apoE levels and lipidation, Aβ pathology, and behavior in a model that expresses human APOE and overproduce Aβ. Methods In vitro, APOE3-glia or APOE4-glia were treated with CS. In vivo, male and female, E3FAD (5xFAD+/−/APOE3 +/+) and E4FAD (5xFAD+/−/APOE4 +/+) mice were treated with CS via intraperitoneal injection at early (from 4 to 8 months of age) and late ages (from 8 to 10 months of age). ApoE levels, ABCA1 levels and, apoE lipidation were measured by western blot and ELISA. Aβ and amyloid levels were assessed by histochemistry and ELISA. Learning and memory were tested by Morris Water Maze and synaptic proteins were measured by Western blot. Results CS treatment increased apoE levels and cholesterol efflux in primary glial cultures. In young male E3FAD mice, CS treatment increased soluble apoE and lipid-associated apoE, reduced soluble oAβ and insoluble Aβ levels as well as Aβ and amyloid deposition, and improved memory and synaptic protein levels. CS treatment did not induce any therapeutic benefits in young female E3FAD and E4FAD mice or in any groups when treatment was started at later ages. Conclusions CS treatment reduced Aβ pathology and improved memory only in young male E3FAD, the cohort with the least AD pathology. Therefore, the degree of Aβ pathology or Aβ overproduction may impact the ability of targeting ABCA1 to be an effective AD therapeutic. This suggests that ABCA1-stabilizing treatment by CS-6253 works best in conditions of modest Aβ levels. |
| first_indexed | 2024-03-08T22:41:54Z |
| format | Article |
| id | doaj.art-f5241d90f3904145ab4ecaa3436a668b |
| institution | Directory Open Access Journal |
| issn | 1758-9193 |
| language | English |
| last_indexed | 2024-03-08T22:41:54Z |
| publishDate | 2023-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Alzheimer’s Research & Therapy |
| spelling | doaj.art-f5241d90f3904145ab4ecaa3436a668b2023-12-17T12:09:08ZengBMCAlzheimer’s Research & Therapy1758-91932023-12-0115111610.1186/s13195-023-01353-zA novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3Ana C. Valencia-Olvera0Deebika Balu1Shreya Bellur2Thomas McNally3Yaseen Saleh4Don Pham5Shivesh Ghura6Jason York7Jan O. Johansson8Mary Jo LaDu9Leon Tai10Department of Anatomy and Cell Biology, University of Illinois at ChicagoDepartment of Anatomy and Cell Biology, University of Illinois at ChicagoDepartment of Anatomy and Cell Biology, University of Illinois at ChicagoDepartment of Surgery, University of WashingtonUniversity of Miami/Jackson Healthcare SystemDepartment of Dentistry, University of Illinois at ChicagoDepartment of Pharmacology, University of PennsylvaniaDepartment of Anatomy and Cell Biology, University of Illinois at ChicagoArtery Therapeutic’s IncDepartment of Anatomy and Cell Biology, University of Illinois at ChicagoDepartment of Anatomy and Cell Biology, University of Illinois at ChicagoAbstract Background Alzheimer’s disease (AD) is characterized by cognitive dysfunction and amyloid plaques composed of the amyloid-beta peptide (Aβ). APOE is the greatest genetic risk for AD with APOE4 increasing risk up to ~ 15-fold compared to APOE3. Evidence suggests that levels and lipidation of the apoE protein could regulate AD progression. In glia, apoE is lipidated via cholesterol efflux from intracellular pools, primarily by the ATP-binding cassette transporter A1 (ABCA1). Therefore, increasing ABCA1 activity is suggested to be a therapeutic approach for AD. CS-6253 (CS) is a novel apoE mimetic peptide that was developed to bind and stabilize ABCA1 and maintain its localization into the plasma membrane therefore promoting cholesterol efflux. The goal of this study was to determine whether CS could modulate apoE levels and lipidation, Aβ pathology, and behavior in a model that expresses human APOE and overproduce Aβ. Methods In vitro, APOE3-glia or APOE4-glia were treated with CS. In vivo, male and female, E3FAD (5xFAD+/−/APOE3 +/+) and E4FAD (5xFAD+/−/APOE4 +/+) mice were treated with CS via intraperitoneal injection at early (from 4 to 8 months of age) and late ages (from 8 to 10 months of age). ApoE levels, ABCA1 levels and, apoE lipidation were measured by western blot and ELISA. Aβ and amyloid levels were assessed by histochemistry and ELISA. Learning and memory were tested by Morris Water Maze and synaptic proteins were measured by Western blot. Results CS treatment increased apoE levels and cholesterol efflux in primary glial cultures. In young male E3FAD mice, CS treatment increased soluble apoE and lipid-associated apoE, reduced soluble oAβ and insoluble Aβ levels as well as Aβ and amyloid deposition, and improved memory and synaptic protein levels. CS treatment did not induce any therapeutic benefits in young female E3FAD and E4FAD mice or in any groups when treatment was started at later ages. Conclusions CS treatment reduced Aβ pathology and improved memory only in young male E3FAD, the cohort with the least AD pathology. Therefore, the degree of Aβ pathology or Aβ overproduction may impact the ability of targeting ABCA1 to be an effective AD therapeutic. This suggests that ABCA1-stabilizing treatment by CS-6253 works best in conditions of modest Aβ levels.https://doi.org/10.1186/s13195-023-01353-zAlzheimer’s diseaseapoECS-6253EFAD mice |
| spellingShingle | Ana C. Valencia-Olvera Deebika Balu Shreya Bellur Thomas McNally Yaseen Saleh Don Pham Shivesh Ghura Jason York Jan O. Johansson Mary Jo LaDu Leon Tai A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3 Alzheimer’s Research & Therapy Alzheimer’s disease apoE CS-6253 EFAD mice |
| title | A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3 |
| title_full | A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3 |
| title_fullStr | A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3 |
| title_full_unstemmed | A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3 |
| title_short | A novel apoE-mimetic increases brain apoE levels, reduces Aβ pathology and improves memory when treated before onset of pathology in male mice that express APOE3 |
| title_sort | novel apoe mimetic increases brain apoe levels reduces aβ pathology and improves memory when treated before onset of pathology in male mice that express apoe3 |
| topic | Alzheimer’s disease apoE CS-6253 EFAD mice |
| url | https://doi.org/10.1186/s13195-023-01353-z |
| work_keys_str_mv | AT anacvalenciaolvera anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT deebikabalu anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT shreyabellur anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT thomasmcnally anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT yaseensaleh anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT donpham anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT shiveshghura anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT jasonyork anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT janojohansson anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT maryjoladu anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT leontai anovelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT anacvalenciaolvera novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT deebikabalu novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT shreyabellur novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT thomasmcnally novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT yaseensaleh novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT donpham novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT shiveshghura novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT jasonyork novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT janojohansson novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT maryjoladu novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 AT leontai novelapoemimeticincreasesbrainapoelevelsreducesabpathologyandimprovesmemorywhentreatedbeforeonsetofpathologyinmalemicethatexpressapoe3 |