Allergy and Alzheimer disease

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive dementia with devastating effects for the patients and their families. The treatments available are purely symptomatic and there is need for treatment strategies aiming at the etiopathogenesis of AD. The effects of systemic inflammation on the development and/or progress of AD are not clarified. Present knowledge points towards both beneficial and detrimental effects of inflammation on AD, depending on both its timing and its nature. Allergy is associated with chronic systemic inflammatory changes, and its effects on the brain are largely unknown. Epidemiological studies have shown that allergic diseases were associated with increased risk for AD. The aim of this thesis was to investigate the effects of allergy on the normal brain and in association with AD-like pathology. In Paper I, we aimed to study whether chronic airway allergy affects the AD-related proteins amyloid precursor protein (APP) and hyperphosphorylated tau (p-tau), and the inflammatory status in the brain of naive mice. We found that allergy increased p-tau levels in the brain, whereas levels of APP were not modified. Furthermore, the levels of immunoglobulin (Ig) G and E were significantly increased in the brain of allergic mice. The increase was not only confined to blood vessels but broadly in the brain parenchyma. We then aimed to study in Paper II the changes in gene expression induced by chronic airway allergy in the brain using microarray technology. Allergy induced changes in several inflammation-related signalling pathways. We found that the levels of insulin-degrading enzyme (IDE) and phosphorylated insulin receptor (p-IR) were decreased in the brain in response to allergy. In Paper III, we investigated the effects of chronic airway allergy on the brain in the 3xTgAD (Tg) mouse model for AD, and their background strain (Bg). The levels of IgG and IgE were also increased in the brain of Tg mice in response to allergy. Allergy increased the levels of C1q component C and interleukin-1β, decreased p-IR, and impaired the burrowing activity in Bg animals. The Tg mice showed increased levels of brain-derived neurotrophic factor and decay-accelerating factor (complement inhibitor), and decreased levels of phosphorylated p38. In paper IV, we analysed the levels of Igs and cytokines in cerebrospinal fluid (CSF) and serum obtained from patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and AD, with or without allergy. The relation of allergy to CSF biomarkers (p-tau, total (t)-tau, and β-amyloid (Aβ)) and mini-mental statement examination (MMSE) was investigated. We found that the CSF levels of IgG1 ratio, IgA and t-tau were lower in AD cases with allergy compared to those without allergy. The serum interferon γ levels were lower while MMSE scores were higher in MCI cases with allergy. In conclusion, our studies suggest that allergy may have negative effects on the normal brain but seemingly beneficial effects in the presence of AD-like pathology. It is possible that stimulation of immune responses induced by allergy may lead to beneficial effects on AD. So far, little is known regarding the association between AD and allergies and further studies are needed to clarify the impact of allergy on AD pathogenesis and progression. ABSTRACT Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive dementia with devastating effects for the patients and their families. The treatments available are purely symptomatic and there is need for treatment strategies aiming at the etiopathogenesis of AD. The effects of systemic inflammation on the development and/or progress of AD are not clarified. Present knowledge points towards both beneficial and detrimental effects of inflammation on AD, depending on both its timing and its nature. Allergy is associated with chronic systemic inflammatory changes, and its effects on the brain are largely unknown. Epidemiological studies have shown that allergic diseases were associated with increased risk for AD. The aim of this thesis was to investigate the effects of allergy on the normal brain and in association with AD-like pathology. In Paper I, we aimed to study whether chronic airway allergy affects the AD-related proteins amyloid precursor protein (APP) and hyperphosphorylated tau (p-tau), and the inflammatory status in the brain of naive mice. We found that allergy increased p-tau levels in the brain, whereas levels of APP were not modified. Furthermore, the levels of immunoglobulin (Ig) G and E were significantly increased in the brain of allergic mice. The increase was not only confined to blood vessels but broadly in the brain parenchyma. We then aimed to study in Paper II the changes in gene expression induced by chronic airway allergy in the brain using microarray technology. Allergy induced changes in several inflammation-related signalling pathways. We found that the levels of insulin-degrading enzyme (IDE) and phosphorylated insulin receptor (p-IR) were decreased in the brain in response to allergy. In Paper III, we investigated the effects of chronic airway allergy on the brain in the 3xTgAD (Tg) mouse model for AD, and their background strain (Bg). The levels of IgG and IgE were also increased in the brain of Tg mice in response to allergy. Allergy increased the levels of C1q component C and interleukin-1β, decreased p-IR, and impaired the burrowing activity in Bg animals. The Tg mice showed increased levels of brain-derived neurotrophic factor and decay-accelerating factor (complement inhibitor), and decreased levels of phosphorylated p38. In paper IV, we analysed the levels of Igs and cytokines in cerebrospinal fluid (CSF) and serum obtained from patients with subjective cognitive impairment (SCI), mild cognitive impairment (MCI) and AD, with or without allergy. The relation of allergy to CSF biomarkers (p-tau, total (t)-tau, and β-amyloid (Aβ)) and mini-mental statement examination (MMSE) was investigated. We found that the CSF levels of IgG1 ratio, IgA and t-tau were lower in AD cases with allergy compared to those without allergy. The serum interferon γ levels were lower while MMSE scores were higher in MCI cases with allergy. In conclusion, our studies suggest that allergy may have negative effects on the normal brain but seemingly beneficial effects in the presence of AD-like pathology. It is possible that stimulation of immune responses induced by allergy may lead to beneficial effects on AD. So far, little is known regarding the association between AD and allergies and further studies are needed to clarify the impact of allergy on AD pathogenesis and progression. LIST OF SCIENTIFIC PAPERS I. Heela Sarlus, Caroline Olgart Hoglund, Bianka Karshikoff, Xiuzhe Wang, Mats Lekander, Marianne Schultzberg, Mircea Oprica. Allergy influences the inflammatory status of the brain and enhances tauphosphorylation. J. Cell. Mol. Med. 2012, 16:2401-2412 II. Heela Sarlus, Xiuzhe Wang, Angel Cedazo-Minguez, Marianne Schultzberg, Mircea Oprica. Chronic airway-induced allergy in mice modifies gene expression in the brain toward insulin resistance and inflammatory responses. J Neuroinflammation. 2013, 10:99 III. Heela Sarlus, Alina Codita, Xiuzhe Wang, Angel Cedazo-Minguez, Marianne Schultzberg, Mircea Oprica. Chronic airway allergy induces anti-inflammatory responses in the brain of 3xTgAD mice. IV. Heela Sarlus, Helga Eyjolfsdottir, Maria Eriksdottir, Mircea Oprica Marianne Schultzberg. Influence of allergy on immunoglobulins and tau in the cerebrospinal fluid of patients with Alzheimer’s disease. LIST OF SCIENTIFIC PAPERS I. Heela Sarlus, Caroline Olgart Hoglund, Bianka Karshikoff, Xiuzhe Wang, Mats Lekander, Marianne Schultzberg, Mircea Oprica. Allergy influences the inflammatory status of the brain and enhances tauphosphorylation. J. Cell. Mol. Med. 2012, 16:2401-2412 II. Heela Sarlus, Xiuzhe Wang, Angel Cedazo-Minguez, Marianne Schultzberg, Mircea Oprica. Chronic airway-induced allergy in mice modifies gene expression in the brain toward insulin resistance and inflammatory responses. J Neuroinflammation. 2013, 10:99 III. Heela Sarlus, Alina Codita, Xiuzhe Wang, Angel Cedazo-Minguez, Marianne Schultzberg, Mircea Oprica. Chronic airway allergy induces anti-inflammatory responses in the brain of 3xTgAD mice. IV. Heela Sarlus, Helga Eyjolfsdottir, Maria Eriksdottir, Mircea Oprica Marianne Schultzberg. Influence of allergy on immunoglobulins and tau in the cerebrospinal fluid of patients with Alzheimer’s disease. CONTENTS