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NF-Кb-Regulated, Proinflammatory Mirnas in Alzheimer's Disease

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NF-Кb-Regulated, Proinflammatory Mirnas in Alzheimer's Disease Lukiw Alzheimer’s Research & Therapy 2012, 4:47 http://alzres.com/content/4/6/47 REVIEW NF-кB-regulated, proinfl ammatory miRNAs in Alzheimer’s disease Walter J Lukiw* Abstract Abundant neurochemical, neuropathological, and genetic evidence suggests that a critical number of proinfl ammatory 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, proinfl ammatory, NF-кB-regulated small noncoding RNAs called miRNAs – have been shown to be signifi cantly 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 proinfl ammatory and pathogenic gene expression programs. The ensuing, progressively altered immune and infl ammatory signaling patterns in AD brain support immunopathogenetic events and proinfl ammatory features of the AD phenotype. This report will briefl y review what is known concerning NF-кB-inducible miRNAs that are signifi cantly upregulated in AD-targeted anatomical regions of degenerating human brain cells and tissues. Quenching of NF-кB-sensitive infl ammatory miRNA signaling using NF-кB-inhibitors such as the polyphenolic resveratrol analog trans-3,5,4’-trihydroxystilbene (CAY10512) may have some therapeutic value in reducing infl ammatory neurodegeneration. Antagonism of NF-кB-inducing, and hence proinfl ammatory, epigenetic and environmental factors, such as the neurotrophic herpes simplex virus-1 and exposure to the potent neurotoxin aluminum, are briefl y 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. Introduction testing [4]. Interestingly, this drug has been shown not Although intensively studied for well over 100 years, the only to attenuate Aβ42 peptide levels but also to lower biological factors that initiate and drive the Alzheimer’s the infl ammatory biomarkers complement factor C3 and disease (AD) process remain incompletely understood monocyte chemotactic protein in the cere brospinal fl uid [1-3]. Anti-AD therapies directed solely against amyloid of patients suff ering from mild cognitive impairment [4]. beta (Aβ) peptides have generally proved extremely Indeed, signifi cant increases in infl am ma tory biomarkers disappointing, although therapeutic strategies targeted such as cytokines, chemokines, com ple ment factors, against multiple AD biomarkers – such as amyloid and chemotactic proteins and C-reactive protein, mito- tau abundance and processing dysfunction and neuro- chondrial-mediated upregulation of reactive oxygen infl ammation – have more recently shown greater species (ROS), and the proinfl ammatory actions of Aβ promise [1-4]. peptides have long been thought to be involved in a As one recent example, the experimental drug posiphen, brain-specifi c infl ammatory process as AD initiates and a chirally pure positive enantiomer of phenserine and β- progresses throughout the limbic system of the brain amyloid precursor protein (βAPP) synthesis inhibitor, has [4-13]. shown a signifi cantly improved effi cacy against multi ple One neurogenetic consequence of increased infl amma- AD-relevant targets, at least in proof-of-princi pal phase I tory signaling in AD brain is the upregulation of the inducible, proinfl ammatory transcription factor NF-кB, *Correspondence: [email protected] and NF-кB-driven miRNA expression; hence a self-sus- Professor of Neurology, Neuroscience and Ophthalmology, LSU Neuroscience taining, self-reinforcing proinfl ammatory signaling loop Center, 2020 Gravier Street, Suite 904, New Orleans, LA 70112, USA is generated [2,3,7-18]. Whether some of these pro- infl am matory signaling systems are neuroprotective or © 2010 BioMed Central Ltd © 2012 BioMed Central Ltd benefi cial to homeostatic brain cell structure and Lukiw Alzheimer’s Research & Therapy 2012, 4:47 Page 2 of 11 http://alzres.com/content/4/6/47 function remains to be clarifi ed [5-9]. Extrinsic and Briefl y, AD is characterized neuropathologically by at environmental factors such as herpes simplex virus-1 least fi ve heterogeneous features, all of which support the (HSV-1) infection and aluminum exposure from the progressive generation of abnormal tau and amyloid, environment, as two exceptionally strong inducers of neural and synaptic defi cits and proinfl ammatory NF-кB and proinfl ammatory miRNA upregulation, are signaling to various degrees. Th ese features include: the considered potential contributors to the development of appearance of hyperphosphorylated tau-protein contain- AD pathology. Major points regarding the potential ing intracellular neurofi brillary tangles; amyloido gene- patho genic role for each of these factors and processes sis – the progressive, age-related generation, aggregation are further discussed in the following sections. and accumulation of Aβ peptides into dense, insoluble, proinfl ammatory and pathogenic deposits of senile Infl ammation and Alzheimer’s disease plaque; reduced synaptic densities and synaptic protein Infl ammation constitutes an intrinsic, physiological assemblies; signifi cant neuronal loss in the temporal lobe defense mechanism aimed at protecting healthy tissues and hippocampal regions that, as AD progresses, radiates from infection, injury and trauma. As such, infl ammation into the more distal parietal, frontal and occipital poles of represents an essential, evolutionarily ancient process the brain; and a unique, chronic and progressive that normally ceases to function once the physiological smoldering infl ammation of the neocortex and limbic insult has been eliminated, and cellular homeostasis has system of the brain, especially in the middle to late stages been restored [1-12]. On the contrary, chronic or sus- of AD [11-18,20-25]. tained infl ammatory signaling contributes to dys- Until recently, the density of neurofi brillary tangle and homeostasis, culminating in progressive cellular damage senile plaque lesions required extensive postmortem as is observed in many pathological and progressive histopathological confi rmation for an accurate diagnosis degenerative conditions ranging from cancer to AD of AD; however, current autoradiographic, nuclear [4,11-18]. magnetic resonance, tomographic and related electronic In the central nervous system (CNS), macrophages and digitization and quantifi cation technologies are capable glial cells – as the primary immune cells in the brain’s of non-invasively and eff ectively resolving these insoluble privileged immune compartment – function primarily, lesions in the aging brains of patients with AD, and in by a variety of phagocytic and digestive mechanisms, to transgenic animal models of AD (Tg-AD) [24-31]. Indeed, promote host defense by maintaining tissue homeostasis the initial aberrant phosphorylation of tau, the generation through the destruction of invading pathogens, through of Aβ peptides, the progressive aggregation from soluble sequestering and eliminating deleterious debris via the Aβ peptide monomers into higher-order structures, and cytoplasmic multi-protein infl ammasome complex, and ultimately into insoluble deposits, and their unusual by promoting tissue repair [12-39]. On the contrary, protease-resistant biophysical properties have been sustained, uncontrolled activation of brain macrophages widely suggested to be the most signifi cant markers for and glial cells can lead to excess production of various early cognitive disturbances, mild cognitive impairment pathogenic factors that contribute to neuronal injury, and early AD onset [12-18,24-32]. Th ese markers may including the signifi cant and dramatic upregulation of typically precede, by decades, the appearance of fully proinfl ammatory chemokines, cytokines and ROS. Th ese mature senile plaque and tangle lesions in the AD brain in turn are capable of activating infl ammatory transcrip- [28-32]. Aβ40 and Aβ42 peptides themselves, and innate tion factors such as NF-кB and proinfl ammatory gene immune system interaction and attack of the mature expression programs that drive cellular fate towards CNS senile plaque and tangle lesions mediated by CNS dys-homeostasis, compromised neuronal function and, macrophages and microglia, may represent one of the ultimately, apoptosis and brain cell death [2,3,38-48]. earliest manifestations of increased immune system A strong association between infl ammation and AD activation and infl ammatory signaling in AD, and of the has been suggested for almost 50 years, and to date at ensuing upregulation of chemokines, cytokines IL-1β and least 2,750 peer-reviewed papers have appeared on the TNFα and others, chemotactic proteins and complement contribution of infl ammation to the AD process [11-14]. factor proteins such as complement factor H (CFH) Some of these infl ammatory processes may be necessary [7-10,32-38]. Th at Aβ40 and Aβ42 peptides directly in an attempt to regain brain cell homeostasis in early activate microglia and monocytes to progressively AD, but the integration of these processes into AD generate these endogenous neurotoxins may signify that proliferation and the progression to late-stage AD is not Aβ peptides or Aβ peptide-containing lesions may be well understood [15-18]. Over the last year there have critical for the initial
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