IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model
Aging is a major risk factor for Alzheimer’s disease (AD). Insulin-like growth factor-1 receptor (IGF-1R) regulates general aging and lifespan. However, the contribution of IGF-1 to age-related AD pathology and progression is highly controversial. Based on our previous work, AβPP/PS1 double transgen...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-07-01
|
| Series: | Frontiers in Cellular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2020.00200/full |
| _version_ | 1818112470817964032 |
|---|---|
| author | Mona Sohrabi Angela M. Floden Gunjan D. Manocha Marilyn G. Klug Colin K. Combs |
| author_facet | Mona Sohrabi Angela M. Floden Gunjan D. Manocha Marilyn G. Klug Colin K. Combs |
| author_sort | Mona Sohrabi |
| collection | DOAJ |
| description | Aging is a major risk factor for Alzheimer’s disease (AD). Insulin-like growth factor-1 receptor (IGF-1R) regulates general aging and lifespan. However, the contribution of IGF-1 to age-related AD pathology and progression is highly controversial. Based on our previous work, AβPP/PS1 double transgenic mice, which express human mutant amyloid precursor protein (APP) and presenilin-1 (PS-1), demonstrated a decrease in brain IGF-1 levels when they were crossed with IGF-1 deficient Ames dwarf mice (df/df). Subsequently, a reduction in gliosis, amyloid-β (Aβ) plaque deposition, and Aβ1–40/42 concentrations were observed in this mouse model. This supported the hypothesis that IGF-1 may contribute to the progression of the disease. To assess the role of IGF-1 in AD, 9–10-month-old male littermate control wild type and AβPP/PS1 mice were randomly divided into two treatment groups including control vehicle (DMSO) and picropodophyllin (PPP), a selective, competitive, and reversible IGF-1R inhibitor. The brain penetrant inhibitor was given ip. at 1 mg/kg/day. Mice were sacrificed after 7 days of daily injection and the brains, spleens, and livers were collected to quantify histologic and biochemical changes. The PPP-treated AβPP/PS1 mice demonstrated attenuated insoluble Aβ1–40/42. Additionally, an attenuation in microgliosis and protein p-tyrosine levels was observed due to drug treatment in the hippocampus. Our data suggest IGF-1R signaling is associated with disease progression in this mouse model. More importantly, modulation of the brain IGF-1R signaling pathway, even at mid-life, was enough to attenuate aspects of the disease phenotype. This suggests that small molecule therapy targeting the IGF-1R pathway may be viable for late-stage disease treatment. |
| first_indexed | 2024-12-11T03:19:27Z |
| format | Article |
| id | doaj.art-a2cf52bfa53c4beb90a805488442e286 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-11T03:19:27Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-a2cf52bfa53c4beb90a805488442e2862022-12-22T01:22:39ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022020-07-011410.3389/fncel.2020.00200506991IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse ModelMona Sohrabi0Angela M. Floden1Gunjan D. Manocha2Marilyn G. Klug3Colin K. Combs4Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United StatesDepartment of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United StatesDepartment of Geriatrics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United StatesDepartment of Population Health, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United StatesDepartment of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, United StatesAging is a major risk factor for Alzheimer’s disease (AD). Insulin-like growth factor-1 receptor (IGF-1R) regulates general aging and lifespan. However, the contribution of IGF-1 to age-related AD pathology and progression is highly controversial. Based on our previous work, AβPP/PS1 double transgenic mice, which express human mutant amyloid precursor protein (APP) and presenilin-1 (PS-1), demonstrated a decrease in brain IGF-1 levels when they were crossed with IGF-1 deficient Ames dwarf mice (df/df). Subsequently, a reduction in gliosis, amyloid-β (Aβ) plaque deposition, and Aβ1–40/42 concentrations were observed in this mouse model. This supported the hypothesis that IGF-1 may contribute to the progression of the disease. To assess the role of IGF-1 in AD, 9–10-month-old male littermate control wild type and AβPP/PS1 mice were randomly divided into two treatment groups including control vehicle (DMSO) and picropodophyllin (PPP), a selective, competitive, and reversible IGF-1R inhibitor. The brain penetrant inhibitor was given ip. at 1 mg/kg/day. Mice were sacrificed after 7 days of daily injection and the brains, spleens, and livers were collected to quantify histologic and biochemical changes. The PPP-treated AβPP/PS1 mice demonstrated attenuated insoluble Aβ1–40/42. Additionally, an attenuation in microgliosis and protein p-tyrosine levels was observed due to drug treatment in the hippocampus. Our data suggest IGF-1R signaling is associated with disease progression in this mouse model. More importantly, modulation of the brain IGF-1R signaling pathway, even at mid-life, was enough to attenuate aspects of the disease phenotype. This suggests that small molecule therapy targeting the IGF-1R pathway may be viable for late-stage disease treatment.https://www.frontiersin.org/article/10.3389/fncel.2020.00200/fullAlzheimer’s diseaseneuroinflammationAβtrophic factorpicropodophyllin |
| spellingShingle | Mona Sohrabi Angela M. Floden Gunjan D. Manocha Marilyn G. Klug Colin K. Combs IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model Frontiers in Cellular Neuroscience Alzheimer’s disease neuroinflammation Aβ trophic factor picropodophyllin |
| title | IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model |
| title_full | IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model |
| title_fullStr | IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model |
| title_full_unstemmed | IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model |
| title_short | IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model |
| title_sort | igf 1r inhibitor ameliorates neuroinflammation in an alzheimer s disease transgenic mouse model |
| topic | Alzheimer’s disease neuroinflammation Aβ trophic factor picropodophyllin |
| url | https://www.frontiersin.org/article/10.3389/fncel.2020.00200/full |
| work_keys_str_mv | AT monasohrabi igf1rinhibitoramelioratesneuroinflammationinanalzheimersdiseasetransgenicmousemodel AT angelamfloden igf1rinhibitoramelioratesneuroinflammationinanalzheimersdiseasetransgenicmousemodel AT gunjandmanocha igf1rinhibitoramelioratesneuroinflammationinanalzheimersdiseasetransgenicmousemodel AT marilyngklug igf1rinhibitoramelioratesneuroinflammationinanalzheimersdiseasetransgenicmousemodel AT colinkcombs igf1rinhibitoramelioratesneuroinflammationinanalzheimersdiseasetransgenicmousemodel |