Relationship between IGF-1 and body weight in inflammatory bowel diseases: Cellular and molecular mechanisms involved

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn''s disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and ß-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology. © 2021 The Author

Proteomic characterization of microglial dysfunction and repair mechanisms in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and it is the most common cause of dementia in the elderly. It is characterized by the presence of extracellular Aβ plaques, intracellular neurofibrillary tangles and neuroinflammation. Despite the incessant efforts to find effective treatments, to date, there is no cure for AD. Microglia, as the brain resident immune cells, are the first line of defense in the brain and contribute to Aβ plaque clearance. Numerous genetic alterations have been identified in microglial genes that confer risk to develop late-onset AD, mainly associated to the deficiency of microglia to clear Aβ plaques. Therefore, the molecular characterization of microglia has become a priority to find novel therapeutic options for AD patients. Different studies have analyzed microglia at the transcriptome level in AD, but this characterization has not been thoroughly performed at the proteome level. In addition, various approaches have been directed to modulate or repair microglial function in AD. However, the molecular signatures of repaired microglia have not been elucidated, which would facilitate the design of more effective microglial immunomodulatory strategies for AD. Thus, in this study, I aimed to characterize microglial proteomic fingerprints along AD progression and to reveal the proteomic signatures of functionally repaired microglia. For the first aim, I analyzed microglia from two different amyloidosis mouse models, the APPPS1 and the APPNL-G-F (APP-KI), at different stages of AD. Mass spectrometry-based proteomic analysis revealed a panel of time-resolved microglial Aβ-response protein changes or MARP signatures, that were commonly regulated in both mouse models, and reflected the molecular changes occurring in microglia during different phases of amyloid accumulation (early, middle and advanced). Interestingly, despite the similar amyloid load observed in both AD models, APPPS1 microglia showed earlier proteomic changes than APP-KI microglia, which correlated with the presence of fibrillar Aβ and phagocytic impairment. This study provides a valuable resource of time-resolved microglial proteome changes along with their functional consequences, which will help to identify novel molecular targets for microglial repair and AD biomarkers. In order to reveal the proteomic signatures of functionally repaired microglia, I used the hematopoietic growth factor GM-CSF, as a microglial immunomodulatory tool, which showed the potential to reduce Aβ load ex vivo and in vivo. Although GM-CSF treatment stimulated microglial phagocytosis and led to a strong reduction of Aβ burden in organotypic brain slices from APP-KI mice, this effect could not be recapitulated in vivo. Accordingly, I could not detect major changes in the microglial proteome upon GM-CSF treatment. Thus, new strategies are needed to unravel the molecular fingerprints of repaired microglia. Despite the challenges to significantly reduce amyloid plaque burden in amyloidosis mouse models, microglia immunomodulation still holds a great potential for the development of effective treatments for AD patients