Publicação
Aging and Alzheimer's disease: Searching for novel molecular cues
| Resumo: | Increased life expectancy contributed to a marked increase in aging-associated maladies. Among those, we can find dementias, which are often accompanied by neurodegeneration and behavioral alterations, and may culminate in a loss of independence and autonomy. Alzheimer's disease (AD) represents the most prevalent form of age-associated dementia and is characterized by severe memory loss and cognitive deficits. This neurodegenerative disease exists as either a less common, early-onset, autosomal dominant familial form and a more prevalent, late-onset, sporadic form. Yet, both types of AD are characterized by common brain pathological hallmarks, namely the presence of extracellular senile plaques, which are highly enriched in different forms of aggregated amyloid beta (Aβ) peptides, and of intracellular neurofibrillary tangles, that result from the aggregation of hyperphosphorylated Tau protein. The discoveries made in the past two decades shed some light on the mechanisms that trigger neuroinflammation, cellular dysfunction and brain pathology, as well as their role as mediators of behavioral alterations, in AD. However, certain aspects of the disease are still poorly understood and are, sometimes, controversial. This thesis emerged with the objective of using different models to explore the role of novel and promising cellular and molecular targets in the context of aging and AD. Initially, we focused on the role of the protein lipocalin 2 (LCN2), which is closely involved in the innate immune response and in iron metabolism, two different mechanisms that can equally modulate the amyloidogenic pathway and Aβ toxicity in AD. Herein, we show that LCN2 is overproduced both in vitro and in vivo by specific brain cell types, namely choroid plexus (CP) epithelial cells and astrocytes, in response to Aβ1-42 peptides. Importantly, we show that the overexpression of iron metabolism and innate-like proinflammatory genes, as well as the marked astrogliosis, observed in response to the toxic levels of Aβ1-42, are ablated in the absence of LCN2. These results point to a role of LCN2 in the modulation of Aβ-induced toxicity and prompt for further investigation regarding the impact of LCN2 on brain pathology and behavior impairment in AD. Next, taking into account the important function of the brain barriers in the maintenance of central nervous system (CNS) homeostasis in health and in disease, we analyzed the response at the level of the blood-cerebrospinal fluid (CSF) barrier, formed by the CP cells, in AD. For that, we took advantage of an AD transgenic mouse model, the PDGFB-APPSwInd (J20) mice, which overexpress the human gene for amyloid precursor protein (APP) with two mutations that favor its amyloidogenic processing and an increased formation of Aβ peptides. Specifically, we analyzed the response in the CP of J20 mice and of age matched wild-type (WT) littermate controls at 3, 5-6 and 11-12 months. By microarray analysis, we found that aging influences different gene pathways in the CP of 11-12 months-old mice, such as the ones involved in the regulation of the cellular circadian cycle, transport of nutrients and lipid metabolism. These alterations support the idea that there is a clear dysfunction of the CP with aging, which impacts on the production of CSF and on the integrity of the blood-CSF barrier. Strikingly, we found an early overexpression of genes implicated in the type I interferon (IFN) response and a decreased expression of the gene encoding for IFN-γ, the major type II IFN cytokine, at later ages, in the CP of J20 mice when compared to age-matched WT mice. Trying to figure out the extent of these changes, we also investigated the response in the brain parenchyma, namely in the dorsal hippocampus (dHPC), and in the periphery, particularly in the liver. Interestingly, the manifestation of deficits in spatial reference-memory by J20 mice, at 3 months, and by WT mice, at 11-12 months, was accompanied by an increased expression of type I IFN genes in the dHPC. Noticeably, we observed a significant correlation between the levels of IFN-α in the CSF and the performance in a memory-dependent task. Regarding the responses in the brain and in the periphery, we found a similar pattern of type II IFN gene expression in the CP and in the liver of J20 mice. However, with aging, there was an overexpression of type I IFN genes and a decrease in the number of perivascular Aβ-loaded macrophages in the liver of J20 mice. These observations suggest that changes in the levels of different types of IFNs may influence the deposition and/or clearance of Aβ, as well as memory and cognition. Altogether, the work presented here highlights some important functions and effects of different types of inflammatory molecules, such as LCN2 and IFNs, in the context of neurodegeneration and of behavioral alterations in AD, opening new doors for future research in the field. |
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| Autores principais: | Mesquita, Sandro Gabriel Ferreira Dá |
| Assunto: | Ciências Médicas::Ciências da Saúde |
| Ano: | 2015 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Increased life expectancy contributed to a marked increase in aging-associated maladies. Among those, we can find dementias, which are often accompanied by neurodegeneration and behavioral alterations, and may culminate in a loss of independence and autonomy. Alzheimer's disease (AD) represents the most prevalent form of age-associated dementia and is characterized by severe memory loss and cognitive deficits. This neurodegenerative disease exists as either a less common, early-onset, autosomal dominant familial form and a more prevalent, late-onset, sporadic form. Yet, both types of AD are characterized by common brain pathological hallmarks, namely the presence of extracellular senile plaques, which are highly enriched in different forms of aggregated amyloid beta (Aβ) peptides, and of intracellular neurofibrillary tangles, that result from the aggregation of hyperphosphorylated Tau protein. The discoveries made in the past two decades shed some light on the mechanisms that trigger neuroinflammation, cellular dysfunction and brain pathology, as well as their role as mediators of behavioral alterations, in AD. However, certain aspects of the disease are still poorly understood and are, sometimes, controversial. This thesis emerged with the objective of using different models to explore the role of novel and promising cellular and molecular targets in the context of aging and AD. Initially, we focused on the role of the protein lipocalin 2 (LCN2), which is closely involved in the innate immune response and in iron metabolism, two different mechanisms that can equally modulate the amyloidogenic pathway and Aβ toxicity in AD. Herein, we show that LCN2 is overproduced both in vitro and in vivo by specific brain cell types, namely choroid plexus (CP) epithelial cells and astrocytes, in response to Aβ1-42 peptides. Importantly, we show that the overexpression of iron metabolism and innate-like proinflammatory genes, as well as the marked astrogliosis, observed in response to the toxic levels of Aβ1-42, are ablated in the absence of LCN2. These results point to a role of LCN2 in the modulation of Aβ-induced toxicity and prompt for further investigation regarding the impact of LCN2 on brain pathology and behavior impairment in AD. Next, taking into account the important function of the brain barriers in the maintenance of central nervous system (CNS) homeostasis in health and in disease, we analyzed the response at the level of the blood-cerebrospinal fluid (CSF) barrier, formed by the CP cells, in AD. For that, we took advantage of an AD transgenic mouse model, the PDGFB-APPSwInd (J20) mice, which overexpress the human gene for amyloid precursor protein (APP) with two mutations that favor its amyloidogenic processing and an increased formation of Aβ peptides. Specifically, we analyzed the response in the CP of J20 mice and of age matched wild-type (WT) littermate controls at 3, 5-6 and 11-12 months. By microarray analysis, we found that aging influences different gene pathways in the CP of 11-12 months-old mice, such as the ones involved in the regulation of the cellular circadian cycle, transport of nutrients and lipid metabolism. These alterations support the idea that there is a clear dysfunction of the CP with aging, which impacts on the production of CSF and on the integrity of the blood-CSF barrier. Strikingly, we found an early overexpression of genes implicated in the type I interferon (IFN) response and a decreased expression of the gene encoding for IFN-γ, the major type II IFN cytokine, at later ages, in the CP of J20 mice when compared to age-matched WT mice. Trying to figure out the extent of these changes, we also investigated the response in the brain parenchyma, namely in the dorsal hippocampus (dHPC), and in the periphery, particularly in the liver. Interestingly, the manifestation of deficits in spatial reference-memory by J20 mice, at 3 months, and by WT mice, at 11-12 months, was accompanied by an increased expression of type I IFN genes in the dHPC. Noticeably, we observed a significant correlation between the levels of IFN-α in the CSF and the performance in a memory-dependent task. Regarding the responses in the brain and in the periphery, we found a similar pattern of type II IFN gene expression in the CP and in the liver of J20 mice. However, with aging, there was an overexpression of type I IFN genes and a decrease in the number of perivascular Aβ-loaded macrophages in the liver of J20 mice. These observations suggest that changes in the levels of different types of IFNs may influence the deposition and/or clearance of Aβ, as well as memory and cognition. Altogether, the work presented here highlights some important functions and effects of different types of inflammatory molecules, such as LCN2 and IFNs, in the context of neurodegeneration and of behavioral alterations in AD, opening new doors for future research in the field. |
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