Intrathecal Chemokine Synthesis in Mild Cognitive Impairment and Alzheimer Disease

Abstract

Background: Immunoreactivity for several chemokines and for their related receptors has been demonstrated in resident cells of the central nervous system, and the up-regulation of some of them is associated with pathological changes found in Alzheimer disease (AD). Objective: To determine interferon-␥-inducible protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), and interleukin 8 (IL-8) levels in cerebrospinal fluid (CSF) from subjects with amnestic mild cognitive impairment (MCI) and patients with AD as compared with agematched controls. Patients: Thirty-eight subjects with amnestic MCI, 36 patients with AD, and 41 age-matched subjects with noninflammatory affections of the nervous system. Design: Evaluation of CSF chemokine production at time of diagnosis of MCI and AD; correlation with clinical and personal data. Longitudinal evaluation of subjects with MCI until conversion to AD. Results: Cerebrospinal fluid IP-10 concentration was significantly increased in patients with MCI and mild AD but not in patients with severe AD (Mini-Mental State Examination score Ͻ15), whereas MCP-1 and IL-8 levels were increased in patients with MCI and all patients with AD. A significant positive correlation between Mini-Mental State Examination score and CSF IP-10 or MCP-1 concentration was observed in patients with AD. No correlation between IP-10 levels and age was found, whereas MCP-1 and IL-8 levels correlated positively with age. Out of 38 subjects with MCI, 19 developed AD within a 1-to 3-year follow-up. Conclusions: The presence of inflammatory molecules is likely to be a very early event in AD pathogenesis, even preceding the clinical onset of the disease, as demonstrated by subjects with MCI who developed AD over time. Interferon-␥-inducible protein 10 is specifically increased in MCI and seems to decrease with the progression of AD, whereas MCP-1 and IL-8 are up-regulated also in late stages of the disease, suggesting a role in phases in which neurodegeneration is prevalent.

Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques

“…IL-8 itself can synergize with Aβ 1-42 to induce PIC and production of the inflammatory enzyme cyclooxygenase-2 in human microglia (Franciosi et al 2005). However, IL-8 concentrations in CSF are substantially higher in aged individuals with amnestic mild cognitive impairment as compared to Alzheimer's disease, but are not correlated with disease duration, and did not change over a 3-year period in people converting from mild cognitive impairment to Alzheimer's disease (Galimberti et al 2006). By extension, IL-8 may facilitate neurodegeneration earlier in the Alzheimer's disease process.…”

“…In a recent report that examined the cytokine profile of aged rhesus monkeys (Asquith et al 2012), there was a similar but nonsignificant trend for higher IL-8 in aged versus adult macaques. IL-8 is also more highly expressed in mild cognitive impairment and Alzheimer's dementia (Galimberti et al 2003(Galimberti et al , 2006. While IL-8 is normally associated with neutrophil activation in the bloodstream, it is a pleiotropic chemokine that is also found in the central nervous system (CNS), where it is released from and predominantly affects microglia and endothelial cells (Ehrlich et al 1998).…”

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

“…These concentrations are likely to reflect pathophysiological conditions because CXCL10 levels in the normal brain are low or undetectable (Mennicken et al, 1999). For example, CXCL10 levels in the CSF of humans under normal conditions are around 100 pg/ml (Galimberti et al, 2006) but can increase as much as 50 fold during pathophysiological conditions such as CNS inflection (Cinque et al, 2005).…”

Chemokine Interleukin-8 (IL-8) in Alzheimer’s and Other Neurodegenerative Diseases

“…Cerebrospinal fluid levels of IL-8 were found significantly elevated in patients with mild cognitive impairment (MCI) and individuals diagnosed with AD compared with age -matched controls [10]. The increased IL-8 in MCI individuals was noteworthy in that MCI may serve as a progression to AD; indeed one-half of MCI patients developed AD within 3 years [10].…”