Publicação
Unraveling the synaptic role of Rab35: implications for Alzheimer’s disease pathology
| Resumo: | Despite considerable progress in the understanding of molecular underpinnings of neuronal malfunction and cognitive impairment associated with Alzheimer’s disease (AD), the physiopathology of the disorder is complex and poorly understood. Chronic environmental stress and the major stress hormones, glucocorticoids (GC), are suggested precipitating factors for AD, and have been shown to trigger APP misprocessing and Aβ production as well as Tau hyperphosphorylation, accumulation and downstream neuronal atrophy and malfunction. However, the mechanisms that regulate intraneuronal trafficking and homeostasis of Aβ & Tau remain poorly understood. Given the critical role of Rab GTPases as master regulators of endosomal protein trafficking, these PhD studies have explored the role of Rabs in Aβ & Tau proteostasis and their significance in AD pathogenesis. We found that the levels of a specific Rab, Rab35, are significantly decreased aged animals, as well in animals exposed to high GC levels or chronic stress, known triggers of APP misprocessing. Using a gain-of-function screen of Rabs that regulate endocytic protein trafficking, we showed that Rab35 is the most potent suppressor of the interaction of APP and BACE, the first enzyme involved in APP misprocessing towards the generation of Aβ. On the contrary, reduced Rab35 may promote the APP misprocessing suggesting Rab35 as an important regulator of the intraneuronal cascade that generates Aβ. In another set of studies of this PhD thesis, we demonstrated for the first time that Rab35 also controls degradation of Tau protein into the endolysosomal pathway through the Rab35-driven induction of the endosomal sorting complex required for transport (ESCRT) machinery. We also detected a phospho-dependent selectivity of Tau sorting into the Rab35/ESCRT pathway, while high GC levels suppress Rab35 expression and ESCRT machinery leading to Tau accumulation on both in vitro and in vivo studies. Importantly, AAV-mediated Rab35 expression rescues both GC-induced Tau accumulation and neuronal atrophy in the hippocampus of experimental animals. Altogether, the findings of these PhD studies suggest an essential role for Rab35 in the intraneuronal mechanisms underlying Aβ generation and Tau accumulation in AD as well as their significance to the precipitating role of chronic stress towards brain pathology. As emerging evidence suggest that the involvement of Tau in multiple neuropathological conditions, including Alzheimer’s disease, frontotemporal dementia, chronic stress and epilepsy, identifying the cellular pathways responsible for Tau intra- and extra-cellular trafficking, as well as positive and negative regulators of these pathways, has broad therapeutic relevance. |
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| Autores principais: | Silva, João Luís Vaz Lima da |
| Assunto: | Ciências Médicas::Ciências da Saúde |
| Ano: | 2019 |
| 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: | Despite considerable progress in the understanding of molecular underpinnings of neuronal malfunction and cognitive impairment associated with Alzheimer’s disease (AD), the physiopathology of the disorder is complex and poorly understood. Chronic environmental stress and the major stress hormones, glucocorticoids (GC), are suggested precipitating factors for AD, and have been shown to trigger APP misprocessing and Aβ production as well as Tau hyperphosphorylation, accumulation and downstream neuronal atrophy and malfunction. However, the mechanisms that regulate intraneuronal trafficking and homeostasis of Aβ & Tau remain poorly understood. Given the critical role of Rab GTPases as master regulators of endosomal protein trafficking, these PhD studies have explored the role of Rabs in Aβ & Tau proteostasis and their significance in AD pathogenesis. We found that the levels of a specific Rab, Rab35, are significantly decreased aged animals, as well in animals exposed to high GC levels or chronic stress, known triggers of APP misprocessing. Using a gain-of-function screen of Rabs that regulate endocytic protein trafficking, we showed that Rab35 is the most potent suppressor of the interaction of APP and BACE, the first enzyme involved in APP misprocessing towards the generation of Aβ. On the contrary, reduced Rab35 may promote the APP misprocessing suggesting Rab35 as an important regulator of the intraneuronal cascade that generates Aβ. In another set of studies of this PhD thesis, we demonstrated for the first time that Rab35 also controls degradation of Tau protein into the endolysosomal pathway through the Rab35-driven induction of the endosomal sorting complex required for transport (ESCRT) machinery. We also detected a phospho-dependent selectivity of Tau sorting into the Rab35/ESCRT pathway, while high GC levels suppress Rab35 expression and ESCRT machinery leading to Tau accumulation on both in vitro and in vivo studies. Importantly, AAV-mediated Rab35 expression rescues both GC-induced Tau accumulation and neuronal atrophy in the hippocampus of experimental animals. Altogether, the findings of these PhD studies suggest an essential role for Rab35 in the intraneuronal mechanisms underlying Aβ generation and Tau accumulation in AD as well as their significance to the precipitating role of chronic stress towards brain pathology. As emerging evidence suggest that the involvement of Tau in multiple neuropathological conditions, including Alzheimer’s disease, frontotemporal dementia, chronic stress and epilepsy, identifying the cellular pathways responsible for Tau intra- and extra-cellular trafficking, as well as positive and negative regulators of these pathways, has broad therapeutic relevance. |
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