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Mechanisms Underlying the Physiological Role of Amyloid Precursor Protein Glutamatergic Synapses /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Mechanisms Underlying the Physiological Role of Amyloid Precursor Protein Glutamatergic Synapses // Joana Isabel Rajao Saraiva.
作者:	Saraiva, Joana Isabel Rajao,
面頁冊數:	1 electronic resource (229 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-07, Section: A.
Contained By:	Dissertations Abstracts International86-07A.
標題:	Physiology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31813437
ISBN:	9798302388315

Mechanisms Underlying the Physiological Role of Amyloid Precursor Protein Glutamatergic Synapses /
Saraiva, Joana Isabel Rajao,

Mechanisms Underlying the Physiological Role of Amyloid Precursor Protein Glutamatergic Synapses /Joana Isabel Rajao Saraiva. - 1 electronic resource (229 pages)

Source: Dissertations Abstracts International, Volume: 86-07, Section: A.

N-methyl-D-aspartate receptors (NMDARs) are glutamatergic ionotropic receptors essential for synaptic maturation during development and synaptic plasticity in adult stages, whose properties are known to change depending on the life stage.In particular, the subunit composition of synaptic NMDARs has important implications for NMDAR function. In the hippocampus, NMDARs are mainly composed by GluN2A or GluN2B subunits, with GluN2B-NMDARs being associated with slower kinetics, more calcium charge transfer and higher mobility.GluN2B-NMDARs are predominant in immature synapses during development, contributing to the synaptic maturation process, which involves a GluN2B to GluN2A shift. Thus, GluN2A-NMDARs are the most abundant subtype in adult stages, when most synapses are in the mature state. Much less is known about the subunit contribution in aged synapses. However, previous reports showed age-related alterations in NMDAR properties, such as slower responses, lower current amplitudes and a negative correlation between GluN2B levels and memory performance.These alterations in NMDAR properties, from development to aging, might be caused by different regulation mechanisms. The amyloid precursor protein (APP), which is mainly known to be involved in Alzheimer's Disease, has emerged as a putative regulator of NMDARs. Although the physiological role of APP is not fully understood, it is known to regulate synaptogenesis and synaptic plasticity and might have different effects when acting through the full-length protein or its derived fragments. Additionally, APP has shown to interact and regulate NMDAR surface levels and currents but the functional relevance of this interaction at different life stages, as well as the underlying mechanisms of regulation have not been explored so far.Thus, we hypothesized that APP regulates NMDARs in an age-dependent manner and defined as the main aims of this work to study APP-NMDAR regulation mechanisms in immature, mature and aged synapses. To address these questions in physiological conditions, we used as our experimental models the hippocampus of wild-type C57Bl/6 mice at different life stages (infant (7-10 days), adults (10-16 weeks) and aged (18 - 20 months), as well as postmortem brain tissue from human subjects with different ages (18-89 years old) and rodent hippocampal primary neuronal cultures.By combining patch-clamp electrophysiology and molecular approaches, we have unraveled a dual mechanism by which APP controls GluN2B-NMDARs, depending on the life stage. In the present study, we show that APP is highly abundant at the post synapse in infant mice, where it interacts with GluN2B-NMDARs, controlling its mediated currents. Moreover, APP knockdown in primary neuronal cultures caused a reduction in GluN2B-NMDAR synaptic content, suggesting that APP might be important to stabilize the receptors at the synapse. Considering the crucial role of GluN2B-NMDAR in synapse maturation, this mechanism might potentially be important to achieve functional, mature synapses during development.Although this interaction is maintained in adult/aged synapses, NMDAR-mediated currents showed to be unaltered when interfering with the APP C-terminal during a short period at these ages, contrary to the results obtained in infant mice. Thus, we concluded that the APP-NMDAR regulatory mechanisms are different in adult/aged mice when compared to infants.

English

ISBN: 9798302388315Subjects--Topical Terms:

518431
Physiology.

Mechanisms Underlying the Physiological Role of Amyloid Precursor Protein Glutamatergic Synapses /
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520 $a N-methyl-D-aspartate receptors (NMDARs) are glutamatergic ionotropic receptors essential for synaptic maturation during development and synaptic plasticity in adult stages, whose properties are known to change depending on the life stage.In particular, the subunit composition of synaptic NMDARs has important implications for NMDAR function. In the hippocampus, NMDARs are mainly composed by GluN2A or GluN2B subunits, with GluN2B-NMDARs being associated with slower kinetics, more calcium charge transfer and higher mobility.GluN2B-NMDARs are predominant in immature synapses during development, contributing to the synaptic maturation process, which involves a GluN2B to GluN2A shift. Thus, GluN2A-NMDARs are the most abundant subtype in adult stages, when most synapses are in the mature state. Much less is known about the subunit contribution in aged synapses. However, previous reports showed age-related alterations in NMDAR properties, such as slower responses, lower current amplitudes and a negative correlation between GluN2B levels and memory performance.These alterations in NMDAR properties, from development to aging, might be caused by different regulation mechanisms. The amyloid precursor protein (APP), which is mainly known to be involved in Alzheimer's Disease, has emerged as a putative regulator of NMDARs. Although the physiological role of APP is not fully understood, it is known to regulate synaptogenesis and synaptic plasticity and might have different effects when acting through the full-length protein or its derived fragments. Additionally, APP has shown to interact and regulate NMDAR surface levels and currents but the functional relevance of this interaction at different life stages, as well as the underlying mechanisms of regulation have not been explored so far.Thus, we hypothesized that APP regulates NMDARs in an age-dependent manner and defined as the main aims of this work to study APP-NMDAR regulation mechanisms in immature, mature and aged synapses. To address these questions in physiological conditions, we used as our experimental models the hippocampus of wild-type C57Bl/6 mice at different life stages (infant (7-10 days), adults (10-16 weeks) and aged (18 - 20 months), as well as postmortem brain tissue from human subjects with different ages (18-89 years old) and rodent hippocampal primary neuronal cultures.By combining patch-clamp electrophysiology and molecular approaches, we have unraveled a dual mechanism by which APP controls GluN2B-NMDARs, depending on the life stage. In the present study, we show that APP is highly abundant at the post synapse in infant mice, where it interacts with GluN2B-NMDARs, controlling its mediated currents. Moreover, APP knockdown in primary neuronal cultures caused a reduction in GluN2B-NMDAR synaptic content, suggesting that APP might be important to stabilize the receptors at the synapse. Considering the crucial role of GluN2B-NMDAR in synapse maturation, this mechanism might potentially be important to achieve functional, mature synapses during development.Although this interaction is maintained in adult/aged synapses, NMDAR-mediated currents showed to be unaltered when interfering with the APP C-terminal during a short period at these ages, contrary to the results obtained in infant mice. Thus, we concluded that the APP-NMDAR regulatory mechanisms are different in adult/aged mice when compared to infants.
520 $a Os recetores N-metil-D-aspartato (NMDARs) sao recetores glutamatergicos ionotropicos, que desempenham um papel fundamental na maturacao e plasticidade sinapticas, sendo que as suas propriedades sao influenciadas pela composicao das subunidades e sofrem alteracoes ao longo da idade.No hipocampo, os recetores NMDA sinapticos pertencem maioritariamente ao subtipo GluN2A ou GluN2B, sendo que o subtipo GluN2B-NMDA esta associado a uma cinetica mais lenta, maior transferencia de carga por calcio e uma maior mobilidade.Os recetores GluN2B-NMDA sao abundantes nas sinapses imaturas durante o desenvolvimento e contribuem para o processo de maturacao sinaptica, fase na qual os recetores GluN2A-NMDAR passam a ser predominantes. Apesar da informacao em relacao a contribuicao relativa destas subunidades para o funcionamento neuronal no envelhecimento ser limitada, ja se comprovou que as propriedades dos recetores NMDA se alteram em idades mais avancadas. Em modelos de roedores, os recetores respondem de forma mais lenta e apresentam menor amplitude de correntes. Alem disso, existe uma correlacao negativa entre os niveis de GluN2B e as capacidades de memoria/ aprendizagem em ratinhos envelhecidos.Estas alteracoes que ocorrem ao longo da idade podem ser causadas por modificacoes nos mecanismos de regulacao dos NMDARs. Em particular, a proteina precursora de amiloide (PPA), extensivamente estudada por estar envolvida na Doenca de Alzheimer, pode funcionar como reguladora dos NMDARs. Apesar de a funcao fisiologica desta proteina nao ser ainda totalmente compreendida, sabe-se que a PPA desempenha um papel importante na sinaptogenese e plasticidade sinaptica. Sabe-se ainda que a PPA atua nao so na sua forma integral, mas tambem atraves dos fragmentos que se geram quando e clivada. Alem disso, foi previamente demonstrado que a PPA interage com os recetores NMDA e tem a capacidade de regular os seus niveis na membrana plasmatica e as suas correntes. No entanto, a relevancia funcional desta interacao, bem como os mecanismos de regulacao ao longo da idade sao ainda desconhecidos.Assim sendo, a nossa hipotese e que a PPA regula os recetores NMDA de uma forma dependente da idade. Logo, definimos como o principal objetivo deste trabalho estudar os mecanismos de regulacao dos recetores NMDA pela PPA em sinapses imaturas, maduras e envelhecidas. De forma a explorar estes mecanismos em condicoes fisiologicas, utilizamos como modelos experimentais o hipocampo de ratinhos C57Bl/6 'wild-type' com diferentes idades (periodo pos-natal (7-10 dias), idade adulta (10-16 semanas) e idade avancada (18 - 20 meses), culturas primarias de neuronios de rato do hipocampo, bem como amostras de tecido cerebral (cortex) humano obtidas postmortem de individuos com idades compreendidas entre 18 e 89 anos.Neste trabalho utilizamos uma combinacao de metodos de eletrofisiologia Patch-Clamp e estudos moleculares, levando a conclusao de que a modulacao exercida pela PPA na funcao dos recetores GluN2B-NMDA apresenta mecansimos diferentes consoante a idade.Os nossos resultados em ratinhos durante o desenvolvimento pos-natal mostraram que a PPA e muito abundante na pos-sinapse, onde interage com os recetores GluN2BNMDA e controla as suas correntes. Alem disso, quando induzimos o silenciamento da PPA em culturas primarias de neuronios, observamos uma reducao na percentagem de subunidades GluN2B que se encontram na pos-sinapse, sugerindo que a PPA pode estabilizar estes recetores na sinapse. Tendo em conta o papel fundamental dos recetores GluN2B-NMDA para a maturacao sinaptica, e possivel que este mecanismo seja importante para obter sinapses funcionais e maduras durante o desenvolvimento.
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650 4 $a Neurons. $3 588699
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650 4 $a Verbal communication. $3 3560678
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