Secretory markers of dense-core vesicles in Alzheimer's disease
[eng] The regulated secretory pathway is a hallmark of professional secretory cells as neurons and endocrine cells. Significant peptidergic neurotransmitters as hormones, neurotrophins and growth factors are targeted to dense-core vesicles (DCVs) and released after stimulation. DCV secretory markers...
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| Tipo de documento: | tese |
| Estado: | Versão publicada |
| Data de publicação: | 2020 |
| País: | España |
| Recursos: | Universidad de Barcelona |
| Repositório: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/184657 |
| Acesso em linha: | https://hdl.handle.net/2445/184657 http://hdl.handle.net/10803/673990 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Secreció Marcadors bioquímics Malaltia d'Alzheimer Neurociències Secretion Biochemical markers Alzheimer's disease Neurosciences |
| Resumo: | [eng] The regulated secretory pathway is a hallmark of professional secretory cells as neurons and endocrine cells. Significant peptidergic neurotransmitters as hormones, neurotrophins and growth factors are targeted to dense-core vesicles (DCVs) and released after stimulation. DCV secretory markers include granins, carboxypeptidases and proprotein convertases and constitute DCV molecular machinery. In addition to their important intracellular roles in sorting, trafficking and processing of peptidergic cargos, extracellular neurotrophic functions have been proposed for certain DCV markers. Of note, variations in some members of the granin family such as chromogranin A (CgA) have been described in the brain and cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients. However, other abundant DCV secretory proteins as the granin SgIII, the enzyme convertase CPE and the proprotein convertases PC1 and PC2, have been poorly studied in AD. Hence, we have analyzed alterations in the secretory markers of DCVs in the brain and CSF of AD patients and in the 5xFAD mouse model of familial AD. As a major finding of the present dissertation, DCV secretory markers accumulate in dystrophic neurites and granulovacuolar degeneration bodies, two prominent neuropathological features of AD. Moreover, DCV secretory proteins markedly decay in the CSF of AD patients, correlating with neurodegeneration and cognitive decline. Furthermore, secretory markers of DCV initially increase and later decrease in the hippocampi and age-dependently decline in the CSF of 5xFAD mice. Additionally, since reactive astrogliosis is a common feature of neurodegenerative diseases, understanding the mechanisms underlying gliotransmission under control and proinflammatory conditions is fundamental. Here we have shown that astrocyte peptidergic secretory vesicles are heterogeneous and display variable release rates in response to Ca2+-mediated stimulation, which are modulated in proinflammatory-treated astrocytes in vitro and in a neuroinflammation model in situ. Besides, unstimulated release of astrocyte secretory proteins in vitro is independent of intrinsic Ca2+ oscillations but critically depends on intracellular Ca2+. Altogether, since neurotransmission and gliotransmission are clearly affected in AD, our results suggest that alterations in the regulated secretory pathway of neurons and astrocytes may participate in underlying pathological mechanisms and propose DCV secretory markers as candidate biomarkers for AD. |
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