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

Conditional expression of human β-hexosaminidase in the neurons of Sandhoff disease rescues mice from neurodegeneration but not neuroinflammation

This study evaluated whether GM(2) ganglioside storage is necessary for neurodegeneration and neuroinflammation by performing β-hexosaminidase rescue experiments in neurons of HexB(−/−) mice. We developed a novel mouse model, whereby the expression of the human HEXB gene was targeted to neurons of HexB(−/−) mice by the Thy1 promoter. Despite β-hexosaminidase restoration in neurons was sufficient in rescuing HexB(−/−) mice from GM(2) neuronal storage and neurodegeneration, brain inflammation persisted, including the presence of large numbers of reactive microglia/macrophages due to persisting GM(2) presence in this cell type. In conclusion, our results suggest that neuroinflammation is not sufficient to elicit neurodegeneration as long as neuronal function is restored

Galactic Cosmic Radiation Leads to Cognitive Impairment and Increased Aβ Plaque Accumulation in a Mouse Model of Alzheimer’s Disease

Galactic Cosmic Radiation consisting of high-energy, high-charged (HZE) particles poses a significant threat to future astronauts in deep space. Aside from cancer, concerns have been raised about late degenerative risks, including effects on the brain. In this study we examined the effects of $^{56}$Fe particle irradiation in an APP/PS1 mouse model of Alzheimer’s disease (AD). We demonstrated 6 months after exposure to 10 and 100 cGy $^{56}$Fe radiation at 1 GeV/µ, that APP/PS1 mice show decreased cognitive abilities measured by contextual fear conditioning and novel object recognition tests. Furthermore, in male mice we saw acceleration of Aβ plaque pathology using Congo red and 6E10 staining, which was further confirmed by ELISA measures of Aβ isoforms. Increases were not due to higher levels of amyloid precursor protein (APP) or increased cleavage as measured by levels of the β C-terminal fragment of APP. Additionally, we saw no change in microglial activation levels judging by CD68 and Iba-1 immunoreactivities in and around Aβ plaques or insulin degrading enzyme, which has been shown to degrade Aβ. However, immunohistochemical analysis of ICAM-1 showed evidence of endothelial activation after 100 cGy irradiation in male mice, suggesting possible alterations in Aβ trafficking through the blood brain barrier as a possible cause of plaque increase. Overall, our results show for the first time that HZE particle radiation can increase Aβ plaque pathology in an APP/PS1 mouse model of AD

Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease

Abstract Neuroinflammation is considered one of the cardinal features of Alzheimer’s disease (AD). Neuritic plaques composed of amyloid β and neurofibrillary tangle-laden neurons are surrounded by reactive astrocytes and microglia. Exposure of microglia, the resident myeloid cell of the CNS, to amyloid β causes these cells to acquire an inflammatory phenotype. While these reactive microglia are important to contain and phagocytose amyloid plaques, their activated phenotype impacts CNS homeostasis. In rodent models, increased neuroinflammation promoted by overexpression of proinflammatory cytokines can cause an increase in hyperphosphorylated tau and a decrease in hippocampal function. The peripheral immune system can also play a detrimental or beneficial role in CNS inflammation. Systemic inflammation can increase the risk of developing AD dementia, and chemokines released directly by microglia or indirectly by endothelial cells can attract monocytes and T lymphocytes to the CNS. These peripheral immune cells can aid in amyloid β clearance or modulate microglia responses, depending on the cell type. As such, several groups have targeted the peripheral immune system to modulate chronic neuroinflammation. In this review, we focus on the interplay of immunomodulating factors and cell types that are being investigated as possible therapeutic targets for the treatment or prevention of AD

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

Response of Oligodendrocyte Progenitor Cells to Single Dose and Fractionated Irradiation: Potential Implications for Central Nervous System Radiation Late Effects

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Environmental Medicine, 2015.Ionizing radiation (IR) is commonly used in the treatment of central nervous system (CNS) cancers and metastases, for cancer prophylaxis, and during bone marrow transplantation. Frequent side effects resulting from normal brain tissue irradiation include impaired cognition, memory, and attention, as well as necrosis and demyelination; these effects can occur months to years following exposure. Over the decades, radiation oncologists have tried to reduce such effects by delivering the required doses of IR broken down into smaller doses given over the course of several weeks, a process referred to as fractionation. Fractionation selectively spares late responding tissues consisting of post-mitotic, differentiated cells. Proliferating normal and tumor tissue are not spared by fractionation due to the predominant response of acute cell death to radiation exposure in proliferating cells; synchronization of the cell cycle and recruitment of quiescent cells may even enhance cell loss by fractionated radiation in proliferative tissue. The brain is considered to be relatively radiation-resistant due to the differentiation of its constituent cell populations. Therefore, fractionation is used in order to minimize late side effects in the CNS. However, the brain contains stem and progenitor populations that may not benefit from a fractionation protocol, like oligodendrocyte progenitor cells (OPCs). Therefore, we hypothesized that a fractionated regimen may induce a similar acute cell loss to an equivalent single dose. Furthermore, despite the potential for recovery, this acute cell loss would result in impaired maturation and reduced myelin integrity and function. To address these hypotheses, Pdgfrα-CreERT2:Rosa26R-YFP mice, which express inducible yellow fluorescent protein (YFP) under the OPC specific platelet derived growth factor receptor-α (PDGFRα) promoter, were exposed to single dose and vii fractionated IR paradigms and examined at time points ranging from 8 hours to 18 months post-irradiation. We found that fractionation induced an acute loss of OPCs due in part to cell cycle synchrony and entry of quiescent cells into the cycle, which are usually associated with early reacting tissue and not thought to occur in the late responding CNS. Furthermore, recovery of OPCs was impaired following fractionated IR compared to single dose exposure, with the time course of recovery being sexdependent. Finally, reduced OPC maturation and myelination, as well as changes in myelin functionality as assessed by corpus callosum conduction, occurred in both single dose and fractionated IR paradigms. Overall, this work demonstrates that fractionation does not spare all normal brain tissue and, importantly, by depleting a vital progenitor cell pool, fractionated schedules may promote greater white matter dysfunction than single dose exposures, a point that should be considered when designing fractionation regimens in radiotherapy. This suggests that the weight of the therapeutic ratio, or ratio of tumor control to normal tissue damage, in fractionated radiation, falls on eliminating tumor cells, and that efforts should be made to limit radiation exposure to normal brain tissue through stereotactic methods in order to reduce side effects

Neuroinflammation and the Glial Response Contribute to Both Beneficial and Pathological Outcomes in Multiple Disease Models

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pathology and Laboratory Medicine, 2015.Neuroinflammation has been considered a driver of pathology and cognitive dysfunction for many years; however, not all inflammation results in the same outcome. The brain is sensitive to a wide variety of inflammatory stimuli that can result in different outcomes depending on the type of exposure, environment, and underlying pathological processes. In order to gain a better understanding of the relationship between neuroinflammation and brain pathology, we developed three models comprising unique inflammatory stimuli. The first model aimed to understand how peripheral inflammation contributes to neuroinflammation. To accomplish this, a 10% total body area full thickness thermal burn was used to induce significant peripheral inflammation without lethality. Prior to burn injury, mice were subjected to 0 or 5 Gy whole body gamma radiation. Typically, only doses over 15 Gy are sufficient to induce neuroinflammation, so a possible combinative effect of combination injury was investigated. Mice were followed out to 6 hours, 1 week, or 6 months. Combination injury resulted in a significant elevation of mRNA for both the vascular marker ICAM-1 and the inflammatory marker TNFα at 6 hours. Interestingly, combination injury also showed increased IL-6 serum protein levels suggesting elevated peripheral inflammation as well. Furthermore, enhanced glial cell activation by CD68 and Iba1 immunohistochemistry was seen at all time points for the combination injury. Lastly, combination injury lead to significant learning and memory deficits compared to the single injuries alone, suggesting a functional synergy between peripheral inflammation arising from burn and brain radiation injury. In addition to cognitive dysfunction, neuroinflammation has been posited to be a driver of pathology in many diseases. One prominent case is Alzheimer’s disease (AD). To explore this relationship, the APP/PS1 AD mouse model was subjected to 0, 10, or 100 cGy 56Fe particle galactic cosmic radiation (GCR). Six months after exposure, irradiated mice showed decreased cognitive abilities. Interestingly, in male mice we observed acceleration of Aβ plaque pathology using Congo red and 6E10 staining, which was confirmed via ELISA. No microglial activation was observed at this time point, but elevated ICAM-1 levels were seen, suggesting a potential vascular mechanism. These two studies suggest that neuroinflammation is a detrimental process leading to cognitive dysfunction and pathology. However, neuroinflammation is a normal response to injury that likely has protective functions. Interestingly, several studies have demonstrated that blocking neuroinflammation does not always mitigate pathology, and in some cases, enhances it. This suggests a more complex nature to neuroinflammation than previously thought. The last model explored these seeming paradoxical findings that in some cases, neuroinflammation can result in amelioration of pathology. Using an adeno-associated viral vector carrying a human IL-1β cDNA to transduce mice, neuroinflammation was induced in one hippocampus of 8-month-old APP/PS1 mice for 4 weeks, while the other hemisphere received a control viral injection. We observed a robust activation of alternatively activated, anti-inflammatory (M2) microglia using the marker Arg1. This increase in Arg1+ microglia coincided with a reduction in Aβ plaques. Arg1+ microglia were shown to contain Aβ suggesting they were the mechanism of clearance. When IL-4 was used to specifically induce Arg1+ microglia, there was significant plaque reduction. Conversely, blocking induction of Arg1+ microglia during chronic inflammation impaired plaque clearance. Together these findings demonstrate that Arg1+ microglia are necessary and sufficient for Aβ plaque reduction during neuroinflammation. Overall, these three models of neuroinflammation provide a better understanding of how inflammation influences both cognitive function and disease progression. Furthermore, they can guide us towards possible avenues for immunomodulatory therapy of brain disorders