Reduced insulin‐induced phosphatidylinositol‐3‐kinase activation in peripheral blood mononuclear leucocytes from patients with Alzheimer's disease

Abstract

The epidemiological finding of an increased risk of dementia in patients with diabetes mellitus has raised the hypothesis that a dysfunction of the insulin receptors plays a role in the pathogenesis of Alzheimer's disease (AD). A possible link is suggested by the evidence that the insulin-stimulated phosphatidylinositol-3-kinase (PI-3-K)/phospho-Akt pathway negatively controls the glycogen synthase kinase-3beta. The activation of this enzyme mediates the hyperphosphorylation of the tau protein, a relevant step in the formation of the neurofibrillary tangles associated with AD. We hypothesized that the neurodegeneration associated with AD is related to an impairment of the intracellular signalling stimulated by insulin receptors. To test this hypothesis we assessed the PI-3-K/phospho-Akt pathway following in-vitro challenge with insulin in peripheral blood mononuclear cells from subjects with AD (n = 20) and controls (n = 20). We found that the stimulation of PI-3-K is blunted in patients with AD with respect to control. The reduction did not correlate with the extent of cognitive decline or with scores at neuropsychological tests exploring attention, memory, language or visuospatial abilities. The study supports the hypothesis that an impaired control of glycogen synthase kinase-3beta activity by insulin receptor-mediated signalling plays a role in the pathogenesis of AD, facilitating tau protein phosphorylation and neurofibrillary tangle formation.

Uncovering Molecular Biomarkers That Correlate Cognitive Decline with the Changes of Hippocampus' Gene Expression Profiles in Alzheimer's Disease

“…Together with the 20 genes mapped to the Insulin signalling pathway KEGG hsa04910 (ACACA, CALM1, CALM3, EIF4E2, FOXO1A, INSR [110], [111], [112], [113], [114], [115], [116], [117], MAPK1, PDE3A, PHKA2, PIK3R1, PIK3R4, PPP1CC, PRKAR2A, PRKAR2B, PRKCI, RHEB, RHOQ, RPS6KB2, SKIP, and TSC2), our results seem to give some support to the hypothesis of altered calcium dynamics [35], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], deregulation of insulin signalling [36], [41], [113], [114], [115], [116], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155], [156], [157], [158], [159], [160], [161], [162], [163]…”

Deficiency in the Inhibitory Serine-Phosphorylation of Glycogen Synthase Kinase-3 Increases Sensitivity to Mood Disturbances

“…We used PBMCs as a surrogate system as lymphocytes in PBMCs express receptors, intracellular signaling proteins, and enzymes that are regulated by many of the same genetic and environmental influences as neurons in the brain (Gladkevich et al , 2004; Tsuang et al , 2005). The expression levels of many classes of biologically relevant processes are similar in PBMCs and brain (Sullivan et al , 2006), as may be the case with GSK3 and its regulatory signaling pathways (Castri et al , 2007; Li et al , 2007a), making PBMCs a valuable human tissue to study signaling systems that also occur in human brain. However, it is clear that further studies are needed to clarify the relationships between the activities of signaling systems in PBMCs and the brain.…”

PI3K/Akt Signal Pathway Involved in the Cognitive Impairment Caused by Chronic Cerebral Hypoperfusion in Rats

“…Moreover several studies have reported an increased risk of dementia in subjects with non-insulin-dependent diabetes mellitus [50]. In order to test this hypothesis, Castri et al [51] analyzed the PI3K/Akt pathway following an in vitro challenge with insulin in peripheral blood mononuclear cells from patients with Alzheimer's disease compared with normal controls. Their major finding is that activation of the PI3K pathway was blunted in the peripheral cells from all of the patients with Alzheimer's disease, independent of the extent of cognitive decline.…”