Inflammatory pathology in neurodegenerative dementias

Abstract

It is estimated that 24 million people worldwide are afflicted with dementia, making it a major public health concern and a research priority. Although treatments which alleviate the symptoms of dementia are available, further research is needed in order to understand the pathogenesis of neurodegenerative dementias and hence produce effective treatments aimed at slowing or even halting disease progression. The majority of neurodegenerative dementias result in cognitive decline, social, speech and motor disturbances. Neurodegenerative dementias have a vast array of pathologies, the most common of which is the intracellular and extracellular aggregation of proteins. Characterised by increased inflammatory cytokines, oxidative molecules and various other pro-inflammatory mediators, inflammation is now recognised as a major pathological event in Alzheimer's disease (AD). A number of prevalent dementias are known to involve inflammatory processes. It is unknown whether inflammation is a primary event in the pathogenesis of dementia, or if these processes are simply a secondary event, intensifying the pathological process. Alzheimer's disease and Frontotemporal lobar degeneration (FTLD) are two neurodegenerative dementias known to demonstrate pathological protein aggregation and inflammatory pathology. Recently, our lab has described novel changes in immunoglobulin immunohistochemistry in the cortex of AD and FTLD tissue. Differences in cytokine type and concentration were observed between the two disorders, which suggest inflammatory processes differ between neurodegenerative dementias. Herein, the aim of this thesis is to characterise immune pathology, with particular focus on inflammation and compare AD with two Frontotemporal dementias. Furthermore, the effect of vitamin D2-enriched Button Mushroom (VDM) ingestion (Agaricus bisporus) on neurodegeneration, memory and behaviour in the APPswe/PS1dE9 mouse model of AD. The results of this work indicate similar patterns of the inflammatory chemokines MCP-1 and IL-8, microglial morphology populations, immunoglobulins and chemokines between AD and FTLD-TDP43, suggesting similar inflammatory pathways in these dementias. Conversely, Pick's disease (PiD), another subtype of FTLD, presented with significantly lower inflammatory pathology than control, AD or FTLD-TDP43 cases, suggesting inflammation may not be a significant process in this disorder. Additionally, no disruptions in blood brain barrier integrity were observed, indicating the increased levels of chemokines, immunoglobulins and complement proteins detected in this study are not from peripheral sources, but likely neuronally derived. Quantification of microglial morphologies revealed both total and activated microglial numbers were unchanged in AD and FTLD-TDP43 pathologies. This would suggest gliosis may not be involved in the superior temporal gyrus (STG) in these disorders. Ramified microglial numbers were significantly lower in AD and FTLD-TDP43 and were positively correlated with neuron numbers in the STG of all diagnostic groups combined. This indicates that a loss of ramified microglia may contribute to neurodegeneration in these disorders and in the healthy brain. PiD cases showed significantly less total, activated and ramified microglia compared with the other diagnostic groups. This may be a result of the extensive tissue loss seen in PiD. Conversely, the extreme loss of microglial populations may result in the rapid neurodegeneration observable in PiD cortex. Two month old wild type (B6C3) and AD transgenic (APPswe/PS1dE9) mice were fed a diet either deficient in vitamin D2 or a diet which was supplemented with VDM, containing 160.2 mg/kg (54 IU/kg) vitamin D2, for 7 months. Effects of the dietary intervention on memory were assessed pre- and post-feeding. Brain sections were evaluated for amyloid I plaque loads, inflammation biomarkers and glial changes using immunohistochemical methods. Compared with mice on the control diet, VDM-fed wild type and AD transgenic mice displayed improved learning and memory, had significantly reduced amyloid plaque load and astrocyte reactivity, and elevated IL-10 in the brain. No feed effects were observed in wild type (WT) mice, whereas ramified microglia were increased in TG-VDM mice compared to TG-Con mice which suggests that VDM feeding conserved ramified microglia in AD pathology. This may account for the improved learning and memory observed in the TG-VDM mice compared to controls. The results suggest that VDM might provide a dietary source of vitamin D2 and other bioactives for preventing pathology and memory-impairment in dementia via modulation of inflammatory pathways and microglial populations. The results from this study identified important similarities and differences between the inflammatory pathways of neurodegenerative dementias. Furthermore this work has highlighted the importance of ramified microglial phenotypes and described novel relationships between morphological populations of microglia in the healthy and demented CNS. Finally, this thesis identifies the multifunctional modulatory effects of vitamin D enriched button mushrooms on an AD mouse model. The findings of this investigation contribute greatly to our understanding of the degenerative processes of inflammatory dementias and have indicated therapeutic measures aimed at decreasing the inflammatory response may result in slowing disease progression and improving quality of life. (RESTRICTED ACCESS, ABSTRACT ONLY)

Date of Award	2014
Original language	English