Neutrophils CD11b and fibroblasts PGE2 are elevated in Alzheimer’s disease (original) (raw)
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Neuroinflammatory perspectives on the two faces of Alzheimer?s disease
Journal of Neural Transmission, 2004
The amyloid plaques in Alzheimer's disease (AD) brains are colocalized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that Ab deposits in AD brains are closely associated with a locally induced, non-immune mediated, chronic inflammatory response. Clinicopathological and neuroradiological studies show that activation of microglia is a relatively early pathogenic event that precedes the process of neuropil destruction in AD. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins that are colocalized with Ab plaques, are genetic risk factors of AD. Epidemiological studies have also shown that the use of classical nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent the risk of AD but clinical trials with anti-inflammatory drugs in AD patients were negative. These findings indicate that anti-inflammatory agents can be helpful in the prevention but not in the treatment of AD. So, pathological, genetic and therapeutic studies suggest that inflammatory mechanisms are most likely involved in the early steps of the pathological cascade. In the autosomal dominant inherited forms of AD the primary factor is the increased production of Ab1-42 resulting into fibrillar Ab deposition that elicits a brain inflammatory response. The etiology of the sporadic forms is yet unknown but this subtype is considered to be heterogeneous and multifactorial in its pathogenesis. Here we review the evidence that inflammation related events could be a critical etiological factor in certain forms of the sporadic AD.
Peripheral Inflammatory Cytokines as Biomarkers in Alzheimer’s Disease and Mild Cognitive Impairment
Neurodegenerative Diseases, 2007
Background: Several lines of evidence in the literature have shown that inflammation is involved in the pathogenesis of Alzheimer’s disease (AD). However, the results from the evaluation of serum inflammatory markers in AD patients have been controversial. Objective: To determine if any differences exist in the monocytic secretion pattern of IL-1β, IL-6, IL-12 and TNF-α from mild cognitive impairment (MCI) and AD patients, when compared with healthy age-matched controls. Methods: To evaluate the percentage of peripheral monocytes secreting IL-1β, IL-6, IL-12 and TNF-α along with the relative levels of these proteins, a cytofluorimetric analysis was conducted under basal conditions and after lipopolysaccharide-induced cell activation. Results: We found, in AD and MCI patients, a significant raise in the percentage of monocytes producing the studied cytokines (under basal conditions and after the exposure to an inflammatory stimulus), as well as a decreased competence of these cells t...
Clinical Relevance: Cytokines in Alzheimer’s Disease
NeuroImmune Biology, 2008
Alzheimer's disease (AD) is a complex interplay between various possible brain insults and the cytokine response resulting in a microlocalized inflammation in predictable areas of the central nervous system (CNS). The process of Alzheimer's is like 'rheumatoid arthritis of the brain'. Progression of AD leads to a total body phenomenon, which leads to death in 8 years on average. Because the illness is multifaceted, treatment and prevention should be as well. Prevention may be possible through the use of daily oral antioxidants to reduce vulnerability to AD. Chronic use of cyclooxygenase (COX)-2 inhibitors could be supported with the onset of pre-Alzheimer's forgetfulness. The use of sex steroids could be considered at about this time. With the onset of illness, anticholinesterase inhibitor is the principal therapy. Selective use of antidepressants should be considered as depression is so frequent in AD. Curiously, there appears to be a role for psychostimulants to treat the atypical depressions seen in AD patients while slowing the progress of AD. 1.
Inflammatory plasma biomarkers in subjects with preclinical Alzheimer’s disease
Alzheimer's Research & Therapy
Background This study investigated plasma biomarkers for neuroinflammation associated with Alzheimer’s disease (AD) in subjects with preclinical AD compared to healthy elderly. How these biomarkers behave in patients with AD, compared to healthy elderly is well known, but determining these in subjects with preclinical AD is not and will add information related to the onset of AD. When found to be different in preclinical AD, these inflammatory biomarkers may be used to select preclinical AD subjects who are most likely to develop AD, to participate in clinical trials with new disease-modifying drugs. Methods Healthy elderly (n= 50; age 71.9; MMSE >24) and subjects with preclinical AD (n=50; age 73.4; MMSE >24) defined by CSF Aβ1-42 levels < 1000 pg/mL were included. Four neuroinflammatory biomarkers were determined in plasma, GFAP, YKL-40, MCP-1, and eotaxin-1. Differences in biomarker outcomes were compared using ANCOVA. Subject characteristics age, gender, and APOE ε4 sta...
Inflammatory markers in Alzheimer's disease and multi-infarct dementia
Mechanisms of Ageing and Development, 2001
Inflammation has been involved in the pathogenesis of dementia. The study evaluates the presence and the source of pro-and anti-inflammatory cytokines in the blood of patients with Alzheimer's disease (AD), multi-infarct dementia (MID) or in non-demented elderly people (controls). Tumor necrosis factor (TNF)-a, interleukin (IL)-1b, IL-6, IL-10, IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor I (sTNF-RI) plasma concentrations and release from blood cells stimulated with lipopolysaccharide (LPS, 1 mg/ml) were determined. The results show that TNF-a released from blood cells is significantly decreased (27%) in all demented patients compared to controls. Circulating TNF-a is increased (400%) only in MID patients. In these patients plasma levels of sTNF-RI are increased (53%) and IL-10 from stimulated blood cells decreased (47%) compared to non-demented subjects. The results show that: (1) peripheral production of TNF-a is blunted in demented (both AD and MID) patients compared to non-demented age-matched subjects; (2) AD patients have a selective disregulation of the peripheral TNF-a system; (3) different cytokines are up-or down-regulated in MID patients showing that in this condition the pro-and anti-inflammatory peripheral cytokine system is more widely affected.
The role of inflammation in Alzheimer's disease
The International Journal of Biochemistry & Cell …, 2005
Considerable evidence gained over the past decade has supported the conclusion that neuroinflammation is associated with Alzheimer's disease (AD) pathology. Inflammatory components related to AD neuroinflammation include brain cells such as microglia and astrocytes, the classic and alternate pathways of the complement system, the pentraxin acute-phase proteins, neuronal-type nicotinic acetylcholine receptors (AChRs), peroxisomal proliferators-activated receptors (PPARs), as well as cytokines and chemokines. Both the microglia and astrocytes have been shown to generate beta-amyloid protein (A), one of the main pathologic features of AD. A itself has been shown to act as a pro-inflammatory agent causing the activation of many of the inflammatory components. Further substantiation for the role of neuroinflammation in AD has come from studies that demonstrate patients who took non-steroidal anti-inflammatory drugs had a lower risk of AD than those who did not. These same results have led to increased interest in pursuing anti-inflammatory therapy for AD but with poor results. On the other hand, increasing amount of data suggest that AChRs and PPARs are involved in AD-induced neuroinflammation and in this regard, future therapy may focus on their specific targeting in the AD brain.
Journal of Alzheimer's disease : JAD, 2011
Neuroinflammation is involved in the pathology of Alzheimer's disease (AD). Our major focus was to clarify whether neuroinflammation plays an important role in AD pathogenesis, particularly prior to the manifestation of overt dementia. We analyzed cytokine expression profiles of the brain, with focus on non-demented patients with increasing AD pathology, referred to as high pathology control (HPC) patients, who provide an intermediate subset between AD and normal control subjects, referred to as low pathology control (LPC) patients. With real-time PCR techniques, we found significant differences in interleukin (IL)-1β, 10, 13, 18, and 33, tumor necrosis factor-α (TNFα) converting enzyme (TACE), and transforming growth factor β1 (TGFβ1) mRNA expression ratios between HPC and AD patients, while no significant differences in the expression ratios of any cytokine tested here were observed between LPC and HPC patients. The cytokine mRNA expression ratios were determined as follows: f...
The significance of neuroinflammation in understanding Alzheimer’s disease
Journal of Neural Transmission, 2006
Neuronal expression of cyclooxygenase-2 (COX-2) and cell cycle proteins is suggested to contribute to neurodegeneration during Alzheimer's disease (AD). The stimulus that induces COX-2 and cell cycle protein expression in AD is still elusive. Activated glia cells are shown to secrete substances that can induce expression of COX-2 and cell cycle proteins in vitro. Using post mortem brain tissue we have investigated whether activation of microglia and astrocytes in AD brain can be correlated with the expression of COX-2 and phosphorylated retinoblastoma protein (ppRb). The highest levels of neuronal COX-2 and ppRb immunoreactivity are observed in the first stages of AD pathology (Braak 0-II, Braak A). No significant difference in COX-2 or ppRb neuronal immunoreactivity is observed between Braak stage 0 and later Braak stages for neurofibrillary changes or amyloid plaques. The mean number of COX-2 or ppRb immunoreactive neurons is significantly decreased in Braak stage C compared to Braak stage A for amyloid deposits. Immunoreactivity for glial markers KP1, CR3/43 and GFAP appears in the later Braak stages and is significantly increased in Braak stage V-VI compared to Braak stage 0 for neurofibrillary changes. In addition, a significant negative correlation is observed between the presence of KP1, CR3/43 and GFAP immunoreactivity and the presence of neuronal immunoreactivity for COX-2 and ppRb. These data show that maximal COX-2 and ppRb immunoreactivity in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia. In contrast to in vitro studies, post mortem data do not support a causal relation between the activation of microglia and astrocytes and the expression of neuronal COX-2 and ppRb in the pathological cascade of AD.