Insulin Suppresses the Expression of Amyloid Precursor Protein, Presenilins, and Glycogen Synthase Kinase-3β in Peripheral Blood Mononuclear Cells

Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo and Kaleida Health, Buffalo, New York 14209, USA.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 03/2011; 96(6):1783-8. DOI: 10.1210/jc.2010-2961
Source: PubMed


Our objective was to determine whether peripheral blood mononuclear cells express amyloid precursor protein (APP) and other mediators involved in the pathogenesis of Alzheimer's disease and whether their expression is suppressed by insulin.
Ten obese type 2 diabetic patients were infused with insulin (2 U/h with 100 ml 5% dextrose/h) for 4 h. Patients were also infused with 5% dextrose/h or normal physiological saline for 4 h, respectively, on two other days as controls. Blood samples were obtained at 0, 2, 4, and 6 h.
Insulin infusion significantly suppressed the expression of APP, presenilin-1, presenilin-2, and glycogen synthase kinase-3β in peripheral blood mononuclear cells. Dextrose and saline infusions did not alter these indices. Insulin infusion also caused significant parallel reductions in nuclear factor-κB binding activity and plasma concentrations of serum amyloid A and intercellular adhesion molecule-1.
A low dose infusion of insulin suppresses APP, presenilin-1, presenilin-2, and glycogen synthase kinase-3β, key proteins involved in the pathogenesis of Alzheimer's disease, in parallel with exerting its other antiinflammatory effects.

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    • "Additionally, many studies have reported abnormal insulin-signaling or insulin-like growth factor I (IGF-1) signaling pathways in AD-associated case studies or cellular experiments. Further support for this comes from clinical study revealing the effectiveness of long-trial intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD [37], [38]. DHCR24 protects MEFs from serum withdrawal-induced apoptosis through its function in cholesterol biosynthesis and maintenance of the structure of caveolae and insulin-Akt-Bad signaling [18]. "
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    ABSTRACT: 3β-Hydroxysteroid-Δ24 reductase (DHCR24) is an endoplasmic reticulum (ER)-localized multifunctional enzyme that possesses anti-apoptotic and cholesterol-synthesizing activities. Accumulating evidence suggests that ER stress is involved in the pathogenesis of neurodegenerative disease. In this study, we investigated whether DHCR24 may function as a neuroprotective protein under ER stress. Neuroblastoma N2A cells were infected with adenovirus expressing myc-tagged DHCR24 (Ad-DHCR24) or lacZ (Ad-lacZ, serving as a control) and subjected to ER-stress, induced with Tunicamycin (TM). Cells infected with Ad-DHCR24-myc were resistant to TM-induced apoptosis, and showed weaker level of caspase-12 activity. These cells also exhibited lower levels of Bip and CHOP proteins than Ad-LacZ-infected cells. Moreover, a stronger and rapid activation of PERK, and a prolonged activation of JNK and p38 were observed in Ad-LacZ-infected cells. The generation of intracellular reactive oxygen species from ER stress was also diminished by the overexpression of DHCR24. Additionally, intracellular cholesterol level was also elevated in the Ad-DHCR24-infected cells, accompanied by a well-organized formation of caveolae (cholesterol-rich microdomain) on the plasma membrane, and improved colocalization of caveolin-1 and insulin-like growth factor 1 receptor. These results demonstrated for the first time that DHCR24 could protect neuronal cells from apoptosis induced by ER stress.
    PLoS ONE 01/2014; 9(1):e86753. DOI:10.1371/journal.pone.0086753 · 3.23 Impact Factor
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    • "It has been shown that increases in the expression levels of amyloid precursor protein, presenilin-1, presenilin-2, and glycogen synthase kinase 3 (GSK3)-β in peripheral blood mononuclear cells derived from type 2 DM patients were efficiently suppressed by insulin infusion. This suppression was accompanied by significant parallel reductions in NF-κB binding activity (Dandona et al. 2011), thus suggesting that insulin may also counteract NF-κB signaling in the brain. "
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    ABSTRACT: Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM.
    Cerebral Cortex 04/2013; 24(9). DOI:10.1093/cercor/bht101 · 8.67 Impact Factor
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    • "Insulin was found to modulate A␤PP expression and processing both in vivo and in vitro. Insulin infusion significantly suppressed the expression of A␤PP, PS1, PS2, and glycogen synthase kinase-3␤ (GSK-3␤) in peripheral blood mononuclear cells of obese individuals with T2D [139]. Insulin and insulin growth factor 1 (IGF- 1) inhibited A␤ production through Akt-mediated phosphorylation/inactivation of GSK-3␤ [140] and prevented abnormal intracellular accumulation of A␤, by increasing its extracellular secretion in brain and accelerating its trafficking from the Golgi and "
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    ABSTRACT: An increasing number of studies have demonstrated a connection between Alzheimer's disease (AD) and diabetes, particularly type 2 diabetes (T2D). The risk for developing T2D and AD increases exponentially with age and having T2D increases the risk of developing AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. This review critically discusses the involvement of mitochondrial abnormalities and oxidative stress in AD and diabetes highlighting the similarities between both pathologies. The impact of insulin resistance/insulin signaling impairment in AD pathogenesis will be also debated. A better understanding of the key mechanisms underlying the interaction between AD and diabetes is needed for the design of effective preventive and therapeutic strategies.
    Journal of Alzheimer's disease: JAD 01/2012; 30 Suppl 2:S199-215. DOI:10.3233/JAD-2011-111127 · 4.15 Impact Factor
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