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

Mona Sohrabi,Angela M Floden,Gunjan D Manocha,Marilyn G Klug,Colin K Combs

doi:10.3389/fncel.2020.00200

Mona Sohrabi, Angela M Floden + Show 3 more

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https://doi.org/10.3389/fncel.2020.00200

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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.

Highlights

Alzheimer’s disease (AD), as the most common form of dementia, comprises 60–80% of all cases (Alzheimer’s Association, 2016)
Enzyme-Linked Immunosorbent Assays (ELISA) indicated a decrease of insoluble Aβ1–40 and soluble/insoluble Aβ1–42 but not soluble Aβ1–40 levels in temporal cortices of AβPP/PS1 mice treated with PPP as levels were no longer significant from wild type controls (Figure 1A)
We observed that reversible pharmacologic inhibition of IGF-1 receptor (IGF-1R) via PPP reduced insoluble Aβ1–40 and soluble/insoluble Aβ1–42 levels in temporal cortices of 9–10-month-old AβPP/PS1 mice

Summary

Introduction

Alzheimer’s disease (AD), as the most common form of dementia, comprises 60–80% of all cases (Alzheimer’s Association, 2016). Since aging is the main risk factor for AD, slowing down this process may delay disease onset or progression (Guerreiro and Bras, 2015). The growth hormone (GH)/insulin-like growth factor (IGF1) signaling pathway is hypothesized to be one of the primary pathways regulating lifespan in general. Partial inactivation of the IGF-1 receptor (IGF-1R) gene or insulin-like signaling extends longevity and postpones age-related dysfunction in nematodes, flies, and rodents (Holzenberger et al, 2003; Tatar et al, 2003; Taguchi et al, 2007; Kappeler et al, 2008; Kenyon, 2010; Xu et al, 2014). Pharmacologic inhibition of the GH/IGF-1 pathway is a promising strategy for impeding or slowing down age-related diseases (Longo et al, 2015)

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