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

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 Aβ 1-40/42 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 Aβ 1-40/42. 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 midlife, 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.

IGF1R Deficiency Modulates Brain Signaling Pathways and Disturbs Mitochondria and Redox Homeostasis

“…The link between the IGF1/IGF1R axis and brain pathologies, particularly AD, has been the topic of significant interest in recent years, with several studies advocating that the modulation of the IGF1R can alter AD-related pathological features, the deposition of amyloid β-peptide (Aβ) and hyperphosphorylated Tau protein. For instance, ablation and/or inhibition of IGF1R from adult neurons was shown to alleviate AD pathology and associated cognitive deficits in transgenic mouse models of the disease [ 48 , 58 , 59 ]. Contrariwise, others reported a diminished Aβ accumulation on AD brains after IGF1 treatment, while IGF1R inhibition aggravated both behavioral and pathological AD symptoms in mice [ 60 , 61 ].…”

From Menopause to Neurodegeneration—Molecular Basis and Potential Therapy

“…The same group also showed that IGF-1R knockout in adult APP/PS1 AD mice results in improved spatial memory and lower accumulation of Aβ-containing autophagic vacuoles [236]. Treatment with picropodophyllin, an IGF-1R inhibitor, attenuated insoluble Aβ and microgliosis in the hippocampi of AβPP/PS1 mice [237]. IGF-1R can form hybrid receptors with insulin receptor (IR), and insulin resistance is one of risk factors of neurodegenerative diseases.…”

“…Considering that oxidative stress and glia-mediated inflammation also contribute to neurodegenerative diseases, the anti-inflammatory effects of IGF-1/IGF-1R still cannot be ruled out. Although IGF-1 suppresses MPTP/MPP +-induced astrocyte activation via GCER [225,264], the IGF-1R inhibitor prevented neuroinflammation in the hippocampus in an AD mouse model [237]. Since MPTP/MPP induced dopaminergic neurotoxicity in a PD model, these controversial results imply that IGF-1/IGF-1R signals might play different roles in PD compared to AD.…”

Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

“…In contrast, IGF-1 delivery (50 mg/kg/day for 1 month) in 11-month-old Tg2576 mice has no beneficial effect on amyloid plaque load or Aβ levels [ 227 ]. Furthermore, inhibition of IGF-1 signaling seems to decrease AD hallmarks [ 228 ]. The administration of a potent inducer of circulating IGF-1 levels (MK-677) also fails to delay AD progression in a randomized trial [ 229 ].…”