Down syndrome (DS) individuals around the age of 40 are more likely to develop Alzheimer¿s disease (AD) than the general population. The precise mechanisms by which trisomy 21 leads to the development of AD-like dementia in DS subjects have not been fully elucidated yet. In AD human brain has been observed an impairment of insulin signaling and increasing evidence supports the involvement of microRNAs (miRNAs) in the neurodegenerative process including AD and DS. In a recent study has been reported that miR-802 (a miRNA encoded on Chr 21) is involved in the onset of insulin resistance in obesity and in T2DM (type 2 diabetes mellitus) mouse models. In this study, we will investigate the role of miR-802 on insulin pathway in human DS brain prior and after AD development and in a mouse model of DS (Ts65Dn) as well. The use of different bioinformatics tools allowed us to identify PTEN and GSK3B as putative miR-802 targets involved in the insulin signaling. We suppose that miR-802 overexpression may occur in DS brain and blocking PTEN and GSK3B translation it may promote an impairment of insulin signaling responsible for the AD cognitive decline in DS adults. To test our hypothesis, we will evaluate the cognitive performance and age-associated changes for miR-802, PTEN and GSK3B as well as the activation state of insulin signaling in the hippocampus and cortex of Ts65Dn and wild type (WT) mice. In addition, we will perform ad hoc in vitro experiments on WT primary neurons to characterize and clarify how the miR-802 overexpression could contribute to develop insulin resistance. To confirm the results obtained in Ts65Dn mice we will evaluate the levels for miR-802, PTEN and GSK3B in human frontal cortex and in hippocampus of DS and DSAD patients. These results will be correlated with the activation state of insulin signaling in order to establish any possible direct or indirect relationships with miR-802 dysregulation and cognitive decline.
Reports from Alzheimer Association highlight that more than 75% of DS individuals aged 65s and older have AD, nearly 6 times the percentage of general population. Different clinical studies have shown a strong correlation between impairment of insulin signaling and neurodegenerative diseases and insulin resistance is now recognized one of the major risk factors for development of AD. Moreover, no evidence is available on the expression and activity of the members of the insulin machinery in DS brain. The proposed research is innovative because it will explore a novel player, miR-802, which is triplicated as a result of trisomy of Chr21 in DS, but no evidence exists on its specific role. Based on published data in T2DM, showing increased expression of miR-802 in hepatocytes, we will investigate if miR-802 overexpression in the brain is associated with insulin resistance and with development of AD neuropathology in DS. We will identify the miR-802 specific targets and their role in the modulation of insulin signaling in the brain
Since the development of AD is virtually inevitable in DS adults, the DS neuropathology can be considered a ¿human prodromal model¿ of early AD and could contribute to understanding the overlapping mechanisms that lead to AD develop in DS but also in general population.
Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin resistance in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Recently, evidence of a tight correlation between neurodegenerative and metabolic diseases has emerged. The novel idea underlying this project is that brain insulin resistance represents a key molecular alteration leading to age-related cognitive decline and may represent a novel target to slow or delay the age- and diet- related cognitive decline. In addition, we will provide novel insight into the ¿genetic background¿ contributing to the onset of insulin resistance. Indeed, no evidence exists on any possible genetic defect associated with impairment of insulin signaling. The results that will emerge from this project are expected to offer a new scenario that will offer the opportunity to develop novel therapeutic strategies in DS to prevent/delay the onset of Alzheimer-like dementia.