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The Role of APC/C-Cdh1 in Alzheimer's disease

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The Role of APC/C-Cdh1 in Alzheimer's disease

dc.contributor.advisor	Lloret Alcañiz, Ana
dc.contributor.advisor	Viña Ribes, José
dc.contributor.author	Fuchsberger, Tanja
dc.contributor.other	Departament de Fisiologia	es_ES
dc.date.accessioned	2016-12-07T10:12:47Z
dc.date.available	2016-12-08T05:45:06Z
dc.date.issued	2016	es_ES
dc.date.submitted	30-11-2016	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/56265
dc.description.abstract	Alzheimer’s disease (AD) is the most common cause of dementia among elderly individuals above 65 years. Estimations suggest that there are currently about 47.5 million people worldwide suffering from dementia, of which 60-70% are AD cases (World Health Organization, 2015). It is an irreversible disease of progressive nature, which leads to deterioration in cognitive functions beyond what is normal in a healthy aging process. Among the affected cognitive functions are memory, thinking skills and orientation. AD is one of the major causes of disability among older people and has a big impact on socio-economical capacities. There is currently no treatment to cure AD and it is a very active field in biomedical research. Numerous new treatments are being tested in various stages of the disease to alter its progressive course. The pathological hallmarks of AD are deposition of plaques of amyloid peptides and the formation of neurofibrillary tangles (NFTs), which are mainly constituted by hyperphosphorylated aggregates of the microtubule-associated protein tau. These accumulations cause damage to cells and trigger progressive, diffuse and massive neuronal loss. The most affected areas are the neocortex, hippocampus, amygdala, and their associated cortices. Moreover, various molecules and signalling pathways are altered in AD, which might contribute substantially to the onset and/or progress of the disease. In this work we analyzed the implication of the E3 ubiquitin ligase, the anaphase promoting complex/cyclosome (APC/C) in AD. APC/C is a large protein complex, forming an E3 RING finger ubiquitin ligase that is one of the main regulators of the cell cycle in proliferating cells. APC/C recognizes proteins by specific amino acid motifs, like KEN-BOX or D-BOX 9 sequences and targets them for degradation. Within the last decade, important neurobiological functions of APC/C and its activator subunits cdh1 and cdc20 have been discovered. It was shown that APC/C is involved in the control of neuronal G0 maintenance, axonal growth, coordinates neurogenesis and synaptic development. Up to date, 15 substrates have been identified, which are directly involved in processes in the nervous system. Accumulation of some of these proteins has been associated with neurodegeneration. In this work we tested the hypothesis that APC/C could have a relevant pathophysiological role in AD. We showed in neurons in primary culture that amyloid beta (Aβ), a peptide related to AD, causes the degradation of cdh1 in a proteasome-dependent manner. This leads to a subsequent increase of the APC/C substrate glutaminase, which causes an elevation of glutamate levels. Increased glutamate levels cause intraneuronal Ca2+ dysregulation, resulting in excitotoxicity and neuronal apoptosis. Glutaminase inhibition prevents these Aβ-induced alterations. Ca2+ dysregulation induced by glutamate causes a similar effect on cdh1 and glutaminase as Aβ. We confirmed these findings in vivo using microinjection of either Aβ or glutamate in the CA1 region of the rat hippocampus. We showed here for the first time in vivo that both, Aβ and glutamate, cause nuclear exclusion of cdh1 and a subsequent increase of glutaminase. These results indicate that maintaining normal APC/C-Cdh1 activity may be a useful target in AD treatment.	en_US
dc.description.abstract	Alzheimer’s disease (AD) is the most common cause of dementia among elderly individuals above 65 years. Estimations suggest that there are currently about 47.5 million people worldwide suffering from dementia, of which 60-70% are AD cases (World Health Organization, 2015). It is an irreversible disease of progressive nature, which leads to deterioration in cognitive functions beyond what is normal in a healthy aging process. Among the affected cognitive functions are memory, thinking skills and orientation. AD is one of the major causes of disability among older people and has a big impact on socio-economical capacities. There is currently no treatment to cure AD and it is a very active field in biomedical research. Numerous new treatments are being tested in various stages of the disease to alter its progressive course. The pathological hallmarks of AD are deposition of plaques of amyloid peptides and the formation of neurofibrillary tangles (NFTs), which are mainly constituted by hyperphosphorylated aggregates of the microtubule-associated protein tau. These accumulations cause damage to cells and trigger progressive, diffuse and massive neuronal loss. The most affected areas are the neocortex, hippocampus, amygdala, and their associated cortices. Moreover, various molecules and signalling pathways are altered in AD, which might contribute substantially to the onset and/or progress of the disease. In this work we analyzed the implication of the E3 ubiquitin ligase, the anaphase promoting complex/cyclosome (APC/C) in AD. APC/C is a large protein complex, forming an E3 RING finger ubiquitin ligase that is one of the main regulators of the cell cycle in proliferating cells. APC/C recognizes proteins by specific amino acid motifs, like KEN-BOX or D-BOX 9 sequences and targets them for degradation. Within the last decade, important neurobiological functions of APC/C and its activator subunits cdh1 and cdc20 have been discovered. It was shown that APC/C is involved in the control of neuronal G0 maintenance, axonal growth, coordinates neurogenesis and synaptic development. Up to date, 15 substrates have been identified, which are directly involved in processes in the nervous system. Accumulation of some of these proteins has been associated with neurodegeneration. In this work we tested the hypothesis that APC/C could have a relevant pathophysiological role in AD. We showed in neurons in primary culture that amyloid beta (Aβ), a peptide related to AD, causes the degradation of cdh1 in a proteasome-dependent manner. This leads to a subsequent increase of the APC/C substrate glutaminase, which causes an elevation of glutamate levels. Increased glutamate levels cause intraneuronal Ca2+ dysregulation, resulting in excitotoxicity and neuronal apoptosis. Glutaminase inhibition prevents these Aβ-induced alterations. Ca2+ dysregulation induced by glutamate causes a similar effect on cdh1 and glutaminase as Aβ. We confirmed these findings in vivo using microinjection of either Aβ or glutamate in the CA1 region of the rat hippocampus. We showed here for the first time in vivo that both, Aβ and glutamate, cause nuclear exclusion of cdh1 and a subsequent increase of glutaminase. These results indicate that maintaining normal APC/C-Cdh1 activity may be a useful target in AD treatment.	es_ES
dc.format.extent	193 p.	es_ES
dc.language.iso	en	es_ES
dc.subject	Alzheimer	es_ES
dc.subject	Ubiquitin ligasas	es_ES
dc.subject	glutamato	es_ES
dc.subject	APC/C-Cdh1	es_ES
dc.title	The Role of APC/C-Cdh1 in Alzheimer's disease	es_ES
dc.type	doctoral thesis	es_ES
dc.subject.unesco	UNESCO::CIENCIAS MÉDICAS	es_ES
dc.embargo.terms	0 days	es_ES