Inflammation and NF-kappa B in Alzheimer's Disease and Diabetes
Department of Molecular Neurobiology, University of Groningen, Haren, The Netherlands. Journal of Alzheimer's disease: JAD
(Impact Factor: 4.15).
02/2009; 16(4):809-21. DOI: 10.3233/JAD-2009-0976
Inflammatory processes are a hallmark of many chronic diseases including Alzheimer's disease and diabetes mellitus. Fairly recent statistical evidence indicating that type 2 diabetes increases the risk of developing Alzheimer's disease has led to investigations of the potential common processes that could explain this relation. Here, we review the literature on how inflammation and the inducible nuclear factor NF-kappaB might be involved in both diabetes mellitus and Alzheimer's disease and whether these factors can link both diseases.
Available from: Zhiyou Cai
- "Increasing research studies have supported that diabetes induced neuroinflammation plays a crucial role in tau and Aβ pathogenesis.12,18,19 Whether such neuroprotective effects of minocycline on diabetic metabolism disorder are through inhibiting inflammation is still unclear. "
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ABSTRACT: Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer's disease, including increased expression of β-amyloid protein (Aβ) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder.
An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Aβ protein, tau phosphorylation, and inflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay.
These results showed that minocycline decreased expression of Aβ protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein.
On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Aβ generation, the decreases in Aβ production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Aβ production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Aβ to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions like diabetes and Alzheimer's disease.
Available from: PubMed Central
- "On the contrary, sustained, uncontrolled activation of brain macrophages and glial cells can lead to excess production of various pathogenic factors that contribute to neuronal injury, including the significant and dramatic upregulation of proinflammatory chemokines, cytokines and ROS. These in turn are capable of activating inflammatory transcription factors such as NF-κB and proinflammatory gene expression programs that drive cellular fate towards CNS dys-homeostasis, compromised neuronal function and, ultimately, apoptosis and brain cell death [2,3,38-48]. "
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ABSTRACT: Abundant neurochemical, neuropathological, and genetic evidence suggests that a critical number of proinflammatory and innate immune system-associated factors are involved in the underlying pathological pathways that drive the sporadic Alzheimer's disease (AD) process. Most recently, a series of epigenetic factors - including a select family of inducible, proinflammatory, NF-κB-regulated small noncoding RNAs called miRNAs - have been shown to be significantly elevated in abundance in AD brain. These upregulated miRNAs appear to be instrumental in reshaping the human brain transcriptome. This reorganization of mRNA speciation and complexity in turn drives proinflammatory and pathogenic gene expression programs. The ensuing, progressively altered immune and inflammatory signaling patterns in AD brain support immunopathogenetic events and proinflammatory features of the AD phenotype. This report will briefly review what is known concerning NF-κB-inducible miRNAs that are significantly upregulated in AD-targeted anatomical regions of degenerating human brain cells and tissues. Quenching of NF-κB-sensitive inflammatory miRNA signaling using NF-κB-inhibitors such as the polyphenolic resveratrol analog trans-3,5,4'-trihydroxystilbene (CAY10512) may have some therapeutic value in reducing inflammatory neurodegeneration. Antagonism of NF-κB-inducing, and hence proinflammatory, epigenetic and environmental factors, such as the neurotrophic herpes simplex virus-1 and exposure to the potent neurotoxin aluminum, are briefly discussed. Early reports further indicate that miRNA neutralization employing anti-miRNA (antagomir) strategies may hold future promise in the clinical management of this insidious neurological disorder and expanding healthcare concern.
Available from: Elena Tamagno
- "We recently demonstrated a novel pathogenic mechanism of AGEs, which contributes to Ab accumulation (Guglielmotto et al. 2010). In streptozotocin rats, as well as in SK-N-BE differentiated neuroblastoma cells, two different AGEs, pentosidine and glyceraldehyde derived pyridinium (GLAP), were able to up-regulate BACE1 expression through their binding with RAGE which is followed by a strong production of ROS and by an activation of the NF-jB pathway, which is a representative Neurotox Res transcription factor activated by RAGE (Granic et al. 2009). Moreover, NF-jB has been recently identified as a molecular intermediate involved in the Ab-mediated control of BACE1. "
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ABSTRACT: Sequential endoproteolytic cleavages operated by the γ-secretase and the β-secretase (BACE1) on the β-amyloid precursor protein result in the production of the β-amyloid (Aβ) species, with two C-terminal variants, at residue 40 or at residue 42. Accumulation in brain tissue of aggregates of Aβ42 is the major pathogenetic event in Alzheimer's disease (AD). The causes of Aβ accumulation in the common sporadic form of AD are not completely understood, but they are likely to include oxidative stress (OS). Data reviewed here shed light on how Aβ generation, oxidative stress, and secretase functions are intimately related in sporadic AD. According to our hypothesis, in sporadic AD, OS resulted from several cellular insults such as aging, hypoxia, hyperglycemia, and hypercholesterolemia-that are well-known risk factors for AD development-can determine a primary induction of γ-secretase and BACE1. The loop proceeds with the generation of Aβ42 and its signaling to BACE1 transcription.
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