Back to Search Start Over

Brain insulin resistance triggers early onset Alzheimer disease in Down syndrome

Authors :
Antonella Tramutola
Chiara Lanzillotta
Fabio Di Domenico
Elizabeth Head
D. Allan Butterfield
Marzia Perluigi
Eugenio Barone
Source :
Neurobiology of Disease, Vol 137, Iss , Pp 104772- (2020)
Publication Year :
2020
Publisher :
Elsevier, 2020.

Abstract

Dysregulation of insulin signaling pathway with reduced downstream neuronal survival and plasticity mechanisms is a fundamental abnormality observed in Alzheimer's disease (AD) brain. This phenomenon, known as brain insulin resistance, is associated with poor cognitive performance and is driven by the uncoupling of insulin receptor (IR) from its direct substrate (IRS1). Considering that Down syndrome (DS) and AD neuropathology share many common features, we investigated metabolic aspects of neurodegeneration, i.e., brain insulin resistance, in DS and whether it would contribute to early onset AD in DS population.Changes of levels and activation of main brain proteins belonging to the insulin signaling pathway (i.e., IR, IRS1, PTEN, GSK3β, PKCζ, AS160, GLUT4) were evaluated. Furthermore, we analyzed whether changes of these proteins were associated with alterations of: (i) proteins regulating brain energy metabolism; (ii) APP cleavage; and (ii) regulation of synaptic plasticity mechanisms in post-mortem brain samples collected from people with DS before and after the development of AD pathology (DSAD) compared with their age-matched controls.We found that DS cases were characterized by key markers of brain insulin resistance (reduced IR and increased IRS1 inhibition) early in life. Furthermore, downstream from IRS1, an overall uncoupling among the proteins of insulin signaling was observed. Dysregulated brain insulin signaling was associated with reduced hexokinase II (HKII) levels and proteins associated with mitochondrial complexes levels as well as with reduced levels of syntaxin in DS cases. Tellingly, these alterations precede the development of AD neuropathology and clinical presentations in DS.We propose that markers of brain insulin resistance rise earlier with age in DS compared with the general population and may contribute to the cognitive impairment associated with the early development of AD in DS.

Details

Language :
English
ISSN :
1095953X
Volume :
137
Issue :
104772-
Database :
Directory of Open Access Journals
Journal :
Neurobiology of Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.7f4047ea78814f98b6ed49028e19bb71
Document Type :
article
Full Text :
https://doi.org/10.1016/j.nbd.2020.104772