Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder of still unknown etiology and the leading cause of dementia worldwide. Besides its main neuropathological hallmarks, a dysfunctional homeostasis of transition metals has been reported to play a pivotal role in the pathogenesis of this disease. Dysregulation of iron (Fe) metabolism in AD has been suggested, particularly at the level of cellular iron efflux. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD. In order to achieve this goal, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed in peripheral blood mononuclear cells (PBMCs) from 73AD patients and 74 controls by quantitative PCR. The results obtained showed a significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid-beta precursor protein (APP; P=0.006) genes in AD patients compared with healthy volunteers. These observations point out to a significant downregulation in the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients, when compared to controls. Taken together, these findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease.

Metalloneurochemistry and the Pierian Spring: ‘Shallow Draughts Intoxicate the Brain’

“…[43] This sequence was confirmed by recent studies showing Tf desaturation [49] and downregulation of ceruloplasmin and APP in the plasma of AD patients, [50] observations consistent with impaired iron export. Thus, iron accumulation appears to be an effect of AD progression.…”

Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics

“…Recently, another study showed significantly the decreased expression of aconitase 1 (ACO1), CP, and APP in peripheral blood mononuclear cells in AD patients as compared to controls, pointing to a down‐regulation of cellular iron export in AD over control (Guerreiro et al . ).…”

“…Recently, application of specialized techniques such as size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS), which enables measurement of iron saturation of proteins such as ferritin or transferrin rather than measurement of total protein levels (Hare et al 2013b), revealed significantly decreased plasma iron in AD patients (Faux et al 2014) because of transferrin desaturation (Hare et al 2015b). Recently, another study showed significantly the decreased expression of aconitase 1 (ACO1), CP, and APP in peripheral blood mononuclear cells in AD patients as compared to controls, pointing to a down-regulation of cellular iron export in AD over control (Guerreiro et al 2015).…”

Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration

“…parietal cortex, motor cortex, and hippocampus (Bartzokis et al, 1994, Bartzokis and Tishler, 2000, Ding et al, 2009, Pfefferbaum et al, 2009, Bilgic et al, 2012, Luo et al, 2013, Langkammer et al, 2014, Tao et al, 2014, Ghadery et al, 2015. Systemic changes in iron homeostasis accompany AD such as decreased iron in plasma, resulting from Tf desaturation, and decreased cellular iron export indicated by decreased expression of aconitase 1, Cp and APP in peripheral blood mononuclear cells of AD patients vs. normal subjects (Faux et al, 2014, Guerreiro et al, 2015, Hare et al, 2013, Hare et al, 2015. Several studies implicate iron in the aggregation, oligomerisation, amyloidosis, and toxicity of Aβ peptides (Mantyh et al, 1993, Schubert and Chevion, 1995, Huang et al, 2004b, Liu et al, 2011.…”