RESUMO
Information exchange executed by extracellular vesicles, including exosomes, is a newly described form of intercellular communication important in the development and physiology of neural systems. These vesicles can be released from cells, are packed with information including signaling proteins and both coding and regulatory RNAs, and can be taken up by target cells, thereby facilitating the transfer of multilevel information. Recent studies demonstrate their critical role in physiological processes, including nerve regeneration, synaptic function, and behavior. These vesicles also have a sinister role in the propagation of toxic amyloid proteins in neurodegenerative conditions, including prion diseases and Alzheimer's and Parkinson's diseases, in inducing neuroinflammation by exchange of information between the neurons and glia, as well as in aiding tumor progression in the brain by subversion of normal cells. This article provides a summary of topics covered in a symposium and is not meant to be a comprehensive review of the subject.
Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Exossomos/fisiologia , Animais , Encéfalo/fisiopatologia , Cílios/fisiologia , Humanos , Invasividade Neoplásica/fisiopatologia , Regeneração Nervosa/fisiologia , Doenças Neurodegenerativas/fisiopatologiaRESUMO
Alzheimer's disease (AD) is characterized by cerebral deposition of ß-amyloid (Aß) peptides, which are generated from amyloid precursor protein (APP) by ß- and γ-secretases. APP and the secretases are membrane associated, but whether membrane trafficking controls Aß levels is unclear. Here, we performed an RNAi screen of all human Rab-GTPases, which regulate membrane trafficking, complemented with a Rab-GTPase-activating protein screen, and present a road map of the membrane-trafficking events regulating Aß production. We identify Rab11 and Rab3 as key players. Although retromers and retromer-associated proteins control APP recycling, we show that Rab11 controlled ß-secretase endosomal recycling to the plasma membrane and thus affected Aß production. Exome sequencing revealed a significant genetic association of Rab11A with late-onset AD, and network analysis identified Rab11A and Rab11B as components of the late-onset AD risk network, suggesting a causal link between Rab11 and AD. Our results reveal trafficking pathways that regulate Aß levels and show how systems biology approaches can unravel the molecular complexity underlying AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Membrana Celular/metabolismo , Endossomos/metabolismo , Exoma , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Células HeLa , Humanos , Transporte Proteico , Proteólise , RNA Interferente Pequeno/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab3 de Ligação ao GTP/genética , Proteínas rab3 de Ligação ao GTP/metabolismoRESUMO
Alzheimer's disease (AD) is characterized by the presence of toxic protein aggregates or plaques composed of the amyloid ß (Aß) peptide. Various lengths of Aß peptide are generated by proteolytic cleavages of the amyloid precursor protein (APP). Mutations in many familial AD-associated genes affect the production of the longer Aß42 variant that preferentially accumulates in plaques. In the case of sporadic or late-onset AD, which accounts for greater than 95% of cases, several genes are implicated in increasing the risk, but whether they also cause the disease by altering amyloid levels is currently unknown. Through loss of function studies in a model cell line, here RNAi-mediated silencing of several late onset AD genes affected Aß levels is shown. However, unlike the genes underlying familial AD, late onset AD-susceptibility genes do not specifically alter the Aß42/40 ratios and suggest that these genes probably contribute to AD through distinct mechanisms.
Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/química , Fragmentos de Peptídeos/genética , Idade de Início , Idoso , Peptídeos beta-Amiloides/genética , Proliferação de Células , Cistatinas/genética , Epistasia Genética , Inativação Gênica , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Células HeLa , Humanos , Modelos Genéticos , Mutação , Placa Amiloide/metabolismo , Interferência de RNA , RiscoRESUMO
Alzheimer's disease (AD) is the most common form of neurodegenerative disease. A characteristic feature of the disease is the presence of amyloid-ß (Aß) which either in its soluble oligomeric form or in the plaque-associated form is causally linked to neurodegeneration. Aß peptide is liberated from the membrane-spanning -amyloid precursor protein by sequential proteolytic processing employing ß- and γ-secretases. All these proteins involved in the production of Aß peptide are membrane associated and hence, membrane trafficking and cellular compartmentalization play important roles. In this review, we summarize the key cellular events that lead to the progression of AD.
