IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model

Sohrabi, Mona and Floden, Angela M. and Manocha, Gunjan D. and Klug, Marilyn G. and Combs, Colin K. (2020) IGF-1R Inhibitor Ameliorates Neuroinflammation in an Alzheimer’s Disease Transgenic Mouse Model. Frontiers in Cellular Neuroscience, 14. ISSN 1662-5102

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Abstract

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.

Item Type: Article
Subjects: STM Digital Press > Medical Science
Depositing User: Unnamed user with email support@stmdigipress.com
Date Deposited: 22 May 2023 05:53
Last Modified: 05 Jul 2024 07:26
URI: http://publications.articalerewriter.com/id/eprint/899

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