Chronic inflammation in brain tissue is an important component of the progression of neurodegenerative conditions such as Alzheimer’s disease. It is important enough that some researchers propose inflammation resulting from persistent infection and cellular senescence to be the primary mechanism in Alzheimer’s disease, and the characteristic accumulation of amyloid-β deposits only a side-effect. Given the failure to achieve meaningful benefits in patients through removal of amyloid-β, researchers are turning their eyes towards ways to suppress inflammatory signaling in the brain. Removal of senescent cells, the source of a great deal of that inflammatory signaling, is one promising avenue, but other efforts focus on interference in specific signaling pathways, as is the case here.

Extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles are Alzheimer’s disease (AD) pathological features hypothesized to lead to neuronal death and cognitive dysfunction. Since aging is the main risk factor for AD, slowing down this process may delay disease onset or progression. The growth hormone (GH)/insulin-like growth factor (IGF-1) 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.

The role of IGF-1 in regulating age-associated AD remains unclear. For instance, lower serum IGF-1 levels correlate with increased cognitive decline and risk of AD. Also, patients with familial AD demonstrate lower levels of circulating IGF-1 compared to controls. An ex vivo study revealed IGF-1 resistance along with insulin resistance through the PI3K pathway in AD patient brains. Finally, IGF-1 treatment diminished Aβ accumulation by improving its transportation out of the brains of AD mouse models while IGF-1R inhibition aggravated both behavioral and pathological AD symptoms in mice. On the other hand, the administration of a potent inducer of circulating IGF-1 levels failed to delay AD progression in a randomized trial. Also, acute or chronic delivery of IGF-1 exerted no beneficial effect on AD pathological hallmarks in rodent models in vivo. Moreover, high levels of serum IGF-1 were detected in individuals diagnosed with AD or other forms of dementia in one study.

Presumably, this dichotomy of effects is, in part, mediated through the effects of IGF-1 on its receptor. The IGF-1R and the insulin receptor (IR) are homologous tyrosine kinase proteins with remarkably different functions. In our previous work, AβPP/PS1 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. Subsequently, a reduction in gliosis and amyloid-β (Aβ) plaque deposition 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: control and picropodophyllin (PPP), a selective, competitive, and reversible IGF-1R inhibitor. 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 amyloid-β. 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.