The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective

Elevation of the proinflammatory cytokine Interleukin-1 (IL-1) is an integral part of the local tissue reaction to central nervous system (CNS) insult. The discovery of increased IL-1 levels in patients following acute injury and in chronic neurodegenerative disease laid the foundation for two decades of research that has provided important details regarding IL-1's biology and function in the CNS. IL-1 elevation is now recognized as a critical component of the brain's patterned response to insults, termed neuroinflammation, and of leukocyte recruitment to the CNS. These processes are believed to underlie IL-1's function in the setting of acute brain injury, where it has been ascribed potential roles in repair as well as in exacerbation of damage. Explorations of IL-1's role in chronic neurodegenerative disease have mainly focused on Alzheimer disease (AD), where indirect evidence has implicated it in disease pathogenesis. However, recent observations in animal models challenge earlier assumptions that IL-1 elevation and resulting neuroinflammatory processes play a purely detrimental role in AD, and prompt a need for new characterizations of IL-1 function. Potentially adaptive functions of IL-1 elevation in AD warrant further mechanistic studies, and provide evidence that enhancement of these effects may help to alleviate the pathologic burden of disease

Osteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to investigate whether localized peripheral inflammation, such as osteoarthritis, contributes to neuroinflammation and neurodegenerative disease <it>in vivo</it>.</p> <p>Methods</p> <p>We employed the inducible Col1-IL1β^XATmouse model of osteoarthritis, in which induction of osteoarthritis in the knees and temporomandibular joints resulted in astrocyte and microglial activation in the brain, accompanied by upregulation of inflammation-related gene expression. The biological significance of the link between peripheral and brain inflammation was explored in the APP/PS1 mouse model of Alzheimer's disease (AD) whereby osteoarthritis resulted in neuroinflammation as well as exacerbation and acceleration of AD pathology.</p> <p>Results</p> <p>Induction of osteoarthritis exacerbated and accelerated the development of neuroinflammation, as assessed by glial cell activation and quantification of inflammation-related mRNAs, as well as Aβ pathology, assessed by the number and size of amyloid plaques, in the APP/PS1; Col1-IL1β^XATcompound transgenic mouse.</p> <p>Conclusion</p> <p>This work supports a model by which peripheral inflammation triggers the development of neuroinflammation and subsequently the induction of AD pathology. Better understanding of the link between peripheral localized inflammation, whether in the form of osteoarthritis, atherosclerosis or other conditions, and brain inflammation, may prove critical to our understanding of the pathophysiology of disorders such as Alzheimer's, Parkinson's and other neurodegenerative diseases.</p

Inflammatory processes in Alzheimer's disease.

peer reviewedGeneration and deposition of amyloid beta peptides and neurofibrillary tangle formation are key mechanisms involved in AD pathogenesis. Recent evidence suggests that inflammatory mechanisms represent a third component which, once initiated by degeneration, may significantly contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzymes are generated and released by microglia, astrocytes and neurons. Degeneration of aminergic brain stem nuclei such as the locus ceruleus and the nucleus baslis of Meynert may facilitate the occurrence of inflammation in their respective projection areas given the antiinflammatory and neuroprotective action of their key products norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate APP processing by upregulation of beta secretase 1 and therefore are able to establish a vicious cycle. Despite the fact that some aspects of inflammation may even exert protective effects to bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal antiinflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. However, the precise molecular mechanism underlying this effect is still being debated. Several mechanisms including inhibition of cyclooxygenase 2, gamma secretase or activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection

The role of COX-1 and COX-2 in Alzheimer's disease pathology and the therapeutic potentials of non-steroidal anti-inflammatory drugs

Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference of the chronic inflammatory reaction in AD. The best-characterised action of NSAIDs is the inhibition of cyclooxygenase (COX). So far, clinical trials designed to inhibit inflammation or cyclooxygenase activity have failed in the treatment of AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in neurodegeneration and AD pathogenesis. Understanding the pathological, physiological and neuroprotective role of cyclooxygenase307 will contribute to the development of a therapy for the treatment or prevention of AD

The Role of Neuroinflammation in the Pathogenesis of Amyotrophic Lateral Sclerosis

Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Interdepartmental Graduate Program in Neuroscience, 2009.Amyotrophic lateral sclerosis (ALS) has remained an incurable disease since its first description by Jean Martin Charcot in 1869. It is characterized by progressive muscle paralysis resulting from degeneration of upper and lower motor neurons in the brain and spinal cord. Despite tremendous progress in the study of this affliction, many facets of the pathologic process leading to neuronal cell death have not been well characterized. Several mechanisms may play a role in the progression of the disease, such as glutamate excitotoxicity, oxidative stress, mitochondrial abnormalities, protein aggregation, and neuroinflammation. This thesis describes how various inflammatory components promote degenerative changes in motor neurons. First, we conducted a comprehensive assessment of neuroinflammatory manifestations throughout the course of ALS in a transgenic mouse model containing a mutant form of superoxide dismutase-1. Using real time quantitative PCR and immunohistochemistry, we prospectively analyzed expression levels of the following molecules: markers of astrocytic and glial activation, GFAP and Iba1, respectively; pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF- α); several components of the prostaglandin signaling cascade including cyclooxygenase-1 (COX-1) and COX-2, together with associated prostaglandin E2 synthases, cPGES and mPGES-1; and intercellular adhesion molecule-1 (ICAM-1), an important mediator of immune interactions between the periphery and the central nervous system. We demonstrate here that the examined indices of neuroinflammation, both at the RNA and protein level, were significantly elevated prior to the onset of clinical manifestations in SOD-1 transgenic mice. The elevation of inflammatory cytokines occurs in parallel with the decline in the number of motor neurons, which are identified by their size and typical morphology as well as positive staining with the specific neuronal marker NeuN. We also detect a significant increase of COX-1 and the associated PGE2 synthase, cPGES. COX-1 is usually considered a constitutively expressed component of the prostaglandin signaling cascade, and we believe that this is the first report suggesting its role in promoting neuroinflammation in a mouse model of ALS. In another series of experiments, we attempted to elucidate the role of PGE2 signaling in mediating cytokine induced degeneration of motor neurons. Using a mixed spinal motor neuron culture, we first established neurocytotoxic effect of IL-1β and TNF-α administration. Following this initial assessment, selective inhibitors of COX-1 and COX-2 were used in order to determine relative contribution of either enzyme to motor neuron death after cytokine treatment. We were able to conclude that COX-1 effectively modulated toxic effects of both IL-1β and TNF-α. In contrast, inhibition of COX-2 did not rescue neurons in the tissue culture. Moreover, treatment of cells with PGE2 replicated toxic effects caused by either IL-1β or TNF-α, suggesting that PGE2 mediates cytokine induced motor neuron degeneration through COX-1 enzymatic activity in a mixed spinal motor neuron culture. PGE2 exerts its biologic activity via interaction with several members of the EP receptor family. Prostaglandin receptor EP1 has been implicated in modulating neurodegenerative changes observed in ischemic brain disease and stroke. Therefore, we used a pharmacologic approach in order to modulate EP1 mediated PGE2 signaling in motor neuron cultures. Antagonism of the EP1 receptor prevented motor neuron degeneration in response to IL-1β, TNF-α, or PGE2. Moreover, in the presence of COX-1 inhibition, stimulation of EP1 signaling produced a marked degree of motor neuron degeneration. The results of this project improve our understanding of the role neuroinflammation plays during progression of ALS in an animal model of the disease, as well as highlight the importance of the prostaglandin signaling cascade and, in particular, prostaglandin EP1 receptors, in promoting inflammatory cytokine mediated motor neuron degeneration. Our hope is that some of the proposed mechanisms of murine motor neuron death may also play a significant role in human ALS. However, given limitations of the models utilized in this work, it remains to be seen whether these findings would ultimately lead to new therapeutic modalities for treating patients with ALS

Cell- and Stage-specific Impact of TNF-alpha Receptor Signaling in Alzheimer's Disease

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pathology, 2013.Alzheimer’s disease (AD) is a progressive degenerative disorder characterized by severe memory loss and cognitive impairment that elaborates in a temporal and spatial manner. Neuropathological correlates include amyloid-beta (Aβ) deposition, neurofibrillary tangles, synaptic loss, and neuronal cell death. AD is the most common form of dementia and lacks truly disease ameliorating therapy. It is estimated that 5.4 million Americans are currently afflicted by AD and as the population ages, the incidence is estimated to increase dramatically. By 2050 it is projected that between 11 and 16 million Americans will be living with the disorder, making research in the diagnosis, treatment, and prevention of this devastating malady a matter of great national importance. Neuroinflammation drives disease AD pathogenesis through the production of proinflammatory molecules and activated glia. Tumor Necrosis Factor- alpha (TNF-α), a pleotropic pro-inflammatory cytokine, is produced in excess and implicated in Aβ- induced inflammation and cognitive decline. While TNF-α has been well studied, its purported function remains elusive, and surprisingly, little is known about the cell type- and stage-specific roles of this signaling molecule in AD. These questions are becoming ever more important since a growing body of research has been devoted to preclinical and clinical testing of non-selective anti-TNF-α modulating drugs for the treatment of AD. Our goal was to dissect the role of TNF-α and its associated receptors to gain insight into the specific signaling requirements and outcomes of this highly multifunctional protein, as a better understanding of TNF-α in AD may facilitate the development of safe and efficacious anti-TNF-α therapeutic interventions. To examine TNF-α signaling requirements, we generated triple transgenic AD (3xTg- AD) mice lacking both TNF-receptor 1 (TNF-RI) and 2 (TNF-RII), the cognate receptors of TNF-α. These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg- AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced Aβ phagocytic marker expression and phagocytosis activity, indicating that intact TNF-α receptor signaling is critical for microglial-mediated uptake of extracellular Aβ peptide pools. Our data suggest that non-selective inhibition of TNF-α for long periods of time (potentially upwards of 20 years or more), where patients might receive anti-TNF-α therapeutics from the onset of symptoms until death, could unintentionally enhance disease severity. In light of our observation revealing that chronic global TNF-α inhibition worsens disease, we subsequently studied the effects of selective TNF signaling regulation in a cell- and stage-specific manner. In the second part of this thesis, we utilized adenoassociated viral (AAV)-vector delivered siRNAs to selectively knockdown neuronal TNF receptor signaling. We demonstrate divergent roles for neuronal TNF-RI and TNF-RII, where suppression of opposing TNF-RII leads to TNF-RI-mediated exacerbation of Aβ and tau pathology in aged 3xTg-AD mice. Interestingly, dampening TNF-RII or both TNF-RI and TNF-RII together leads to a stageindependent increase of Iba1-positive microglial staining implying that neuronal TNF-RII may act non-cell autonomously on the microglial cell population. These results reveal that TNF receptor signaling is complex and it is unlikely that all cells and both receptors will respond positively to broad anti-TNF-α treatments at various stages of disease. In aggregate, our data support the development of cell-, stage-, and/or receptor-specific anti-TNF-α therapeutics for AD

AAV gene therapy vectors in the TMJ

Abstract Objectives The goal of this project was to evaluate the use of two adeno‐associated viral vector serotypes, adeno‐associated viral vectors (AAV)‐2 and AAV‐6, approved for and used for gene therapy in humans, for the delivery of therapeutic genes to the temporomandibular joint (TMJ) and the attendant sensory nerves. Methods Young adult wild‐type C57BL/6 mice were intra‐articularly inoculated with AAV‐2 and AAV‐6 encoding the reporter gene gfp, the expression of which was assessed in the TMJ as well as along nerves innervating the TMJ. Results AAV‐2 and AAV‐6 serotypes were characterized by varying levels of tissue tropism demonstrating different efficacy of infection for articular chondrocytes, meniscal fibroblasts, and trigeminal neurons. Specifically, AAV‐2 infected both neurons and articular chondrocytes/meniscal fibroblasts, whereas AAV‐6 showed selectivity primarily for neurons. Conclusions The results of this study are clinically significant in the successful application of gene therapy vectors for TMJ disorders, as this new knowledge will allow for appropriate targeting of specific therapeutic genes to selective tissues (neurons vs. chondrocytes/fibroblasts) as needed by using specific viral vector serotypes

The Effect of Sustained Overexpression of Interleukin-1β on Pathology in Murine Models of Alzheimer’s disease and Tauopathy

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neurobiology and Anatomy, 2014.Alzheimer’s disease (AD) is the most common form of dementia in the elderly and is marked by extraneuronal beta Amyloid (Aβ) plaques and intraneuronal tangles of abnormally phosphorylated Tau (Neurofibrillary Tangles or NFTs) in the brain. Abnormally phosphorylated tau and NFTs can cause a separate class of neurodegenerative conditions known as tauopathies. Sustained neuroinflammation accompanies pathogenesis in most of these diseases including AD, and is marked by elevated cytokines, chemokines and gliosis in the brain. Interleukin 1 (IL-1), a major proinflammatory cytokine was found to be specifically elevated in AD and Down’s syndrome brains. IL-1 was proposed to form a cytokine cycle with Aβ that once turned on, drives AD pathology. We set out to obtain direct evidence for the role of sustained upregulation of Interleukin- 1β (IL-1β) in regulating both amyloid and tau pathology using the triple transgenic mouse model of Alzheimer’s disease (3xTgAD mice), which demonstrate both plaques and tangles with age. To this end we made use of an inducible murine model of sustained IL-1β overexpression developed in our laboratory. 3xTgAD/IL-1βXAT mice demonstrated a 4-6-fold elevation in phospho-tau pathology despite a 70-80% reduction in amyloid burden after one and three months of IL-1β overexpression. 3xTgAD/IL-1βXAT mice also showed upregulated Glycogen Synthase Kinase β (GSK3β) and p38 Mitogen Activated Protein Kinase (p38MAPK), both potential tau kinases, after one month of IL-1β overexpression. To avoid any confounds arising from a transgenic model overexpressing both amyloid and tau, we overexpressed IL-1β in JNPL3 mice, which overexpress human tau with the P301L mutation. JNPL3/IL-1βXAT mice demonstrated a similar increase in phospho-tau pathology after one and three months of IL-1β overexpression without changing the expression of transgenic tau. Suppressing the production of prostaglandin E2 by treating JNPL3/IL-1βXAT mice with SC560, a selective COX-1 inhibitor reversed the IL-1β mediated exacerbation of tau pathology. Therefore, we found direct evidence suggesting that IL-1β mediated neuroinflammation exacerbates tau pathology, and reducing neuroinflammation by targeting COX-1 can have therapeutic advantages in tauopathies. Our studies in the 3xTgAD mice also demonstrate that neuroinflammation can be a doubleedged sword in Alzheimer’s and immunomodulatory therapies in AD need to be approached cautiously

Inhibition of Adult Hippocampal Neurogenesis by Sustained Interleukin-1B

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Neurobiology & Anatomy, 2012.Neurogenesis persists throughout adulthood in rodents and is speculated to be important in learning and memory, responses to stress, repair/regeneration, and normal maintenance of the adult CNS. Alterations in adult hippocampal neurogenesis have been observed in numerous neurological diseases that contain a neuroinflammatory component. Interleukin-1 (IL-1) is a pro-inflammatory cytokine that contributes to neuroinflammation in many CNS disorders and could play an important role in modulating adult hippocampal neurogenesis. Indeed, IL-1 has been recently shown to negatively affect adult hippocampal neurogenesis when infused acutely into the cerebroventricular system. Furthermore, there is evidence that IL-1 can bind directly to neural precursors to cause cell cycle arrest in vitro. Despite this information, little is known about the effects of sustained neuroinflammation, as occurs in neurodegenerative and other disorders, on adult hippocampal neurogenesis. Our results reveal a severe reduction in adult hippocampal neurogenesis due to focal and chronic expression of IL-1 in a transgenic mouse model, IL-1XAT, that evokes a complex neuroinflammatory response. Furthermore, we found that sustained IL-1 caused a skewing of cell fate from a neuronal to astroglial lineage. Running, a known stimulus for adult neurogenesis, was not beneficial in increasing neurogenesis in the presence of sustained IL-1 expression. In addition, conditional knockout of an adapter protein necessary for IL-1 signaling, MyD88, in nestin+ neural precursor cells (NPCs) did not prevent the IL-1-induced reduction in neuroblasts. Interestingly, MyD88 deficiency in nestin+ NPCs caused an increase in astrogliosis in the presence of IL-1, suggesting that MyD88-dependent signaling is important in limiting astroglial differentiation due to inflammation. In the absence of inflammation, MyD88 deficiency did not alter the fate of NPCs. Thus, sustained IL-1 causes a reduction in adult hippocampal neurogenesis that is unlikely due to a direct effect on nestin+ NPCs