Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid β Clearance

Abstract

Obesity is a risk factor for Alzheimer’s disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid β (Aβ) in overweight mice because its systemic elimination may impact brain Aβ load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aβ clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aβ accumulation by the liver, the major site of elimination of systemic Aβ, but unaltered brain Aβ levels. We also found that Aβ accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aβ accumulation—ameliorated by IGF-I administration, and unchanged brain Aβ levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aβ precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPβ ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of Aβ without affecting brain Aβ load. Increased serum IGF-I likely contributes to enhanced peripheral Aβ clearance in overweight mice, without affecting brain Aβ load probably because its brain entrance is reduced.

Gamma frequency light flicker regulates amyloid precursor protein trafficking for reducing β‐amyloid load in Alzheimer's disease model

“…To elucidate whether 40 Hz light flicker reduces Aβ production, we examined its effects on APP cleavage by measuring levels of the cleavage intermediates of APP, sAPPα, soluble amyloid precursor protein β (sAPPβ), and Aβ in APP/PS1 male mice (Figure 1c). Using the sAPPβ and sAPPα as markers of amyloidogenic and non‐amyloidogenic pathway (Herrero‐Labrador et al, 2020), respectively, we found that stimulation with 40 Hz light flicker significantly reduced sAPPβ (Figure 1d) and Aβ (Figure 1f), but increased sAPPα (Figure 1e) and sAPPα/sAPPβ ratio (Figure g), compared with those of dark control and 80 Hz light flicker. We next determined if 40 Hz light flicker altered APP‐proteolytic processing in APP/PS1 female mice (Figure b).…”

Application of Artificial Intelligence Modeling Technology Based on Fluid Biopsy to Diagnose Alzheimer’s Disease

“…For example, in a European cohort study, a machine-learning approach identified 347 plasma metabolites associated with early diagnosis in AD with an area under curve (AUC) of about 0.85 ( Stamate et al, 2019 ). In a study of circulating non-coding RNA in patients with AD, 21 disease-related features were identified using RT-qPCR, and 18 strongly correlated features were extracted using statistical learning methods to establish a machine learning model, with an AUC of about 0.86 ( Herrero-Labrador et al, 2020 ). In an AD classifier based on texture features, the researchers modeled the high-level semantic features of MRI with an accuracy of about 85% ( So et al, 2019 ).…”

Metabolic Diffusion in Neuropathologies: The Relevance of Brain-Liver Axis

“…BDNF is related to metabolism and synaptic plasticity, whereas IGF-1 supports nerve growth differentiation, synaptic plasticity and neurotransmitter synthesis and release. The development of hyperglycemia and insulin resistance, which often have a metabolic origin due to bad dietary habits, leads to a reduction of IGF-1 production and an impairment of cognitive function ( Anlar et al, 1999 ; Gómez-Pinilla, 2008 ; Torres Aleman, 2012 ; Herrero-Labrador et al, 2020 ).…”