IGF-1R Inhibition Reduces Neuroinflammation in an Alzheimer's Mouse Model
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.
I refer all to Reason's excellent previous post on IGF-1 and aging...
Also, from the cited paper...
"The AβPP/PS1 model demonstrates robust plaque deposits but no p-tau containing neurofibrillary tangles as a limitation that may ultimately alter our ability to extrapolate findings to human disease."
"Despite changes in gliosis and Aβ levels [small effects in the transgenic mice only], we observed no alteration of brain cytokine levels due to PPP [IGF-1R inhibitor] treatment"
"Collectively, these data illustrate the complexity of IGF-1 and its associated receptor in mediating changes in the transgenic mice and suggest that anti-amyloid therapeutic strategies that interfere with IGF-1R signaling may be dependent upon age, particular cell type, disease state, and even the conformation of Aβ."
"These studies suggest distinct roles of IGF-1R in different cell types that support both potentiating and attenuating functions during disease. Human and AD mouse model studies also demonstrate the dichotomous effects of IGF-1R in AD."
The way I look at it, to get a robust 100 year old with the body of a 50 year old, you probably need that 100 year old to have 50ish sex and growth hormone (and IGF-1) levels. So we need to understand what tricks are needed to maintain/support such levels, not promote their lowering, even if the latter might get us a few more years of decrepitude. :)