Dysregulated NF-κB Pathway in Peripheral Mononuclear Cells of Alzheimers Disease Patients

Abstract

Diagnosis and therapeutic strategies in Alzheimer's disease (AD) might greatly benefit of the present multidisciplinary approach for studying the molecular pathogenesis of the disorder. Gene expression profile at peripheral level could be a promising tool for pathogenic studies as well as for early diagnosis of AD. A dysregulated inflammatory response, as well as other systemic disorders, have been described in AD. Therefore, we investigated the expression, at peripheral level, of a number of genes involved in the inflammatory, oxidative stress and proliferative response of a well defined, small cohort of sporadic AD patients. Firstly, the mRNA expression of inflammatory, stress and proliferation/ differentiation genes were evaluated, using SuperArray, in mitogen-stimulated peripheral blood mononuclear cells (PBMC) from a group of 12 well-characterized, sporadic AD patients with various levels of dementia, by comparison with aged-matched controls. Real-time RT-PCR confirmed the trend of alteration in 16 genes out of the 36 supposed to be dysregulated in AD patients, by the preliminary screening. The expression level of the NFKB1(p105/50Kd) gene was significantly higher in AD with respect to adult age-matched controls (AA) and was related to the Mini-Mental State Examination (MMSE) score of the same patients. In addition, the expression of various NF-κB target genes and of both NF-κBp50 and NF-κBp65 DNA-binding activity were increased in PBMC from AD patients in comparison with those from AA. Our results suggest that NF-κB activation at peripheral blood cell level could be a potential new hallmark of AD progression and sustain a rationale to more deeply investigate the therapeutic potential of specific NF-κB inhibitors in AD.

Regulation of RAGE splicing by hnRNP A1 and Tra2β‐1 and its potential role in AD pathogenesis

“…Increasing evidence indicates that AD is characterized by multiple dysregulation at peripheral blood mononuclear cell level (Ascolani et al . ; Serini et al . ; Zhang et al .…”

“…The relationship between the altered alternative splicing of mRAGE and esRAGE in PBMCs from AD patients Increasing evidence indicates that AD is characterized by multiple dysregulation at peripheral blood mononuclear cell level (Ascolani et al 2012;Serini et al 2012;Zhang et al 2012;Villa et al 2013). We investigated the expression of mRAGE and esRAGE at peripheral blood level during AD pathogenesis by analyzing the ratio of mRAGE and esRAGE variants in PBMCs from 7 AD patients and six healthy old people as the control.…”

Habitual physical exercise has beneficial effects on telomere length in postmenopausal women

“…40,41 Circulating mononuclear cells are mitotic cells, capable of proliferation. 42 In addition, proinflammatory/oxidant genes or transcription factor expression in PBMCs has been shown to increase under certain conditions such as old age and with cardiometabolic disorders such as hypertension, 43 Alzheimer disease, 44 and diabetic nephropathy. 45 However, the connection between exercise and oxidative stress or inflammation has long been debated.…”

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration

“…This indicates that similar type of immune responses occur in the brain and periphery, and show the communication between the brain and peripheral immune systems. An interesting study demonstrated upregulation of nuclear factor-kappaB (NF-κB) activation in the peripheral blood mononuclear cells in AD patients thereby suggesting NF-κB inhibitors as therapeutic agents in AD patients (Ascolani et al, 2012). Imbalance of peripheral T cell subsets (decreased CD8 + and increased CD4 + cells) has been reported in AD patients indicating peripheral immune response in AD (Shalit et al, 1995); this is similar to a previous report on brain tumor patients that showed altered peripheral immune parameters in patients with a brain tumor (Kempuraj et al, 2004a).…”