Publicação
The role of signaling lipids in the nervous system physiology and pathology: mechanistic insights of the phospholipase D pathway in neurodegenerative diseases
| Resumo: | Lipids are a major constituent of the brain and, more specifically, signaling lipids have been shown to regulate brain functioning. Moreover, lipid signaling modulation has been demonstrated to be a potential therapeutic option for neurological disorders, such as Alzheimer’s disease (AD). AD is the most common neurodegenerative disease and currently there is no effective treatment to tackle its progression. Therefore, a detailed understanding of its pathogenesis is critical to envision new therapeutic strategies. The main hallmarks of AD are the accumulation of amyloid-beta (Aβ) and impaired phosphorylation of tau. Growing evidence suggests that a group of enzymes called phospholipases, that modulate the metabolism of signaling lipids, have an impact in neuronal physiology, including membrane trafficking processes. The lipid modifying phospholipase D (PLD) isoenzymes, PLD1 and PLD2, were shown to affect endocytosis and membrane trafficking, as well as modulate AD-related signaling pathways. Moreover, Aβ was reported to increase both isoenzymes’ activity in primary neuronal cultures and in an AD mouse model. Despite this, the precise role of PLD enzymes in AD pathology is poorly understood. We envisioned a multidisciplinary approach using neuronal cell lines, nematode and AD mouse models for further characterization of the role of the PLD pathway in neurodegenerative diseases. While we found that ablation of PLD has no important effect in worm behavior, its ablation in an AD-like model that overexpresses mutated Aβ markedly improves various of its phenotypes. Additionally, we showed that PLD enzymes and tau interact and that PLD overexpression leads to decreased tau levels in a cell line model. Remarkably, PLD ablation in a C. elegans tauopathy-like model led to an increase in tau levels and marked improvement of various of its phenotypes. We also found that tau interacts with several phospholipids, such as phosphatidic acid, the product of PLD enzymatic activity. Collectively, our results support PLD as a downstream pathway of Aβ interaction with membranes, identifies the PLD pathway as a key regulator of tau physiology and pathology and confirms PLD as an important player in neurodegeneration in tauopathy disease models. To further address the role of PLD pathway as a key regulator in neurodegenerative diseases, future studies should be performed to dissect the mechanism underlying its neuroprotective effect. Furthermore, it has been shown that AD patients are more susceptible to seizure-like activity and have a higher rate of epileptiform/sub-epileptic events. The use of AD mouse models (hAPP) mice, with Aβ overproduction, replicates many of the human disease hallmarks, such as memory deficits and susceptibility to pharmacological induced seizures. Concerning AD pathogenesis, it has been shown that specific lipid signatures have been identified both in human and mouse AD brain samples, showing that lipid metabolism is indeed dysregulated. We characterized the hippocampal lipidome of hAPP mice in the context of pharmacologically-induced seizures. With our unbiased lipidomic approach, we observed overall major lipid changes in hAPP mice in line with previous reports. Importantly, lipid profiling of the hAPP mouse brain hippocampus in the context of pharmacologically-induced seizures allowed for the identification of the dysregulated lipid pathways, revealing putative targets for pharmacological intervention that may potentially be used to protect from excitotoxicity in an AD context. In summary, our work further suggests that PLD is a potential therapeutic target for neurodegenerative diseases and support the notion that lipid signaling is a promising target for pharmacological intervention in excitotoxicity pathological diseases. |
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| Autores principais: | Bravo, Ana Francisca Rodrigues Vaz |
| Assunto: | Alzheimer’s Disease Lipids PLD C.elegans Doença de Alzheimer Lípidos |
| Ano: | 2018 |
| 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: | Lipids are a major constituent of the brain and, more specifically, signaling lipids have been shown to regulate brain functioning. Moreover, lipid signaling modulation has been demonstrated to be a potential therapeutic option for neurological disorders, such as Alzheimer’s disease (AD). AD is the most common neurodegenerative disease and currently there is no effective treatment to tackle its progression. Therefore, a detailed understanding of its pathogenesis is critical to envision new therapeutic strategies. The main hallmarks of AD are the accumulation of amyloid-beta (Aβ) and impaired phosphorylation of tau. Growing evidence suggests that a group of enzymes called phospholipases, that modulate the metabolism of signaling lipids, have an impact in neuronal physiology, including membrane trafficking processes. The lipid modifying phospholipase D (PLD) isoenzymes, PLD1 and PLD2, were shown to affect endocytosis and membrane trafficking, as well as modulate AD-related signaling pathways. Moreover, Aβ was reported to increase both isoenzymes’ activity in primary neuronal cultures and in an AD mouse model. Despite this, the precise role of PLD enzymes in AD pathology is poorly understood. We envisioned a multidisciplinary approach using neuronal cell lines, nematode and AD mouse models for further characterization of the role of the PLD pathway in neurodegenerative diseases. While we found that ablation of PLD has no important effect in worm behavior, its ablation in an AD-like model that overexpresses mutated Aβ markedly improves various of its phenotypes. Additionally, we showed that PLD enzymes and tau interact and that PLD overexpression leads to decreased tau levels in a cell line model. Remarkably, PLD ablation in a C. elegans tauopathy-like model led to an increase in tau levels and marked improvement of various of its phenotypes. We also found that tau interacts with several phospholipids, such as phosphatidic acid, the product of PLD enzymatic activity. Collectively, our results support PLD as a downstream pathway of Aβ interaction with membranes, identifies the PLD pathway as a key regulator of tau physiology and pathology and confirms PLD as an important player in neurodegeneration in tauopathy disease models. To further address the role of PLD pathway as a key regulator in neurodegenerative diseases, future studies should be performed to dissect the mechanism underlying its neuroprotective effect. Furthermore, it has been shown that AD patients are more susceptible to seizure-like activity and have a higher rate of epileptiform/sub-epileptic events. The use of AD mouse models (hAPP) mice, with Aβ overproduction, replicates many of the human disease hallmarks, such as memory deficits and susceptibility to pharmacological induced seizures. Concerning AD pathogenesis, it has been shown that specific lipid signatures have been identified both in human and mouse AD brain samples, showing that lipid metabolism is indeed dysregulated. We characterized the hippocampal lipidome of hAPP mice in the context of pharmacologically-induced seizures. With our unbiased lipidomic approach, we observed overall major lipid changes in hAPP mice in line with previous reports. Importantly, lipid profiling of the hAPP mouse brain hippocampus in the context of pharmacologically-induced seizures allowed for the identification of the dysregulated lipid pathways, revealing putative targets for pharmacological intervention that may potentially be used to protect from excitotoxicity in an AD context. In summary, our work further suggests that PLD is a potential therapeutic target for neurodegenerative diseases and support the notion that lipid signaling is a promising target for pharmacological intervention in excitotoxicity pathological diseases. |
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