RESUMO
Alzheimer's disease (AD) is the most common form of dementia in the elderly. It is generally believed that ß-amyloidogenesis, tau-hyperphosphorylation, and synaptic loss underlie cognitive decline in AD. Rps23rg1, a functional retroposed mouse gene, has been shown to reduce Alzheimer's ß-amyloid (Aß) production and tau phosphorylation. In this study, we have identified its human homolog, and demonstrated that RPS23RG1 regulates synaptic plasticity, thus counteracting Aß oligomer (oAß)-induced cognitive deficits in mice. The level of RPS23RG1 mRNA is significantly lower in the brains of AD compared to non-AD patients, suggesting its potential role in the pathogenesis of the disease. Similar to its mouse counterpart, human RPS23RG1 interacts with adenylate cyclase, activating PKA/CREB, and inhibiting GSK-3. Furthermore, we show that human RPS23RG1 promotes synaptic plasticity and offsets oAß-induced synaptic loss in a PKA-dependent manner in cultured primary neurons. Overexpression of Rps23rg1 in transgenic mice consistently prevented oAß-induced PKA inactivation, synaptic deficits, suppression of long-term potentiation, and cognitive impairment as compared to wild type littermates. Our study demonstrates that RPS23RG1 may reduce the occurrence of key elements of AD pathology and enhance synaptic functions to counteract oAß-induced synaptic and cognitive deficits in AD.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/metabolismo , Agregados Proteicos , Agregação Patológica de Proteínas/metabolismo , Proteínas Ribossômicas/metabolismo , Sinapses/metabolismo , Adenilil Ciclases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Animais , Sequência de Bases , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Clonagem Molecular , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Potenciação de Longa Duração/genética , Camundongos , Camundongos Transgênicos , Plasticidade Neuronal , Neurônios/metabolismo , Fosforilação , Ligação Proteica , RNA Mensageiro/genética , Proteínas Ribossômicas/química , Proteínas Ribossômicas/genética , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Sorting nexin 27 (SNX27), a brain-enriched PDZ domain protein, regulates endocytic sorting and trafficking. Here we show that Snx27(-/-) mice have severe neuronal deficits in the hippocampus and cortex. Although Snx27(+/-) mice have grossly normal neuroanatomy, we found defects in synaptic function, learning and memory and a reduction in the amounts of ionotropic glutamate receptors (NMDA and AMPA receptors) in these mice. SNX27 interacts with these receptors through its PDZ domain, regulating their recycling to the plasma membrane. We demonstrate a concomitant reduced expression of SNX27 and CCAAT/enhancer binding protein ß (C/EBPß) in Down's syndrome brains and identify C/EBPß as a transcription factor for SNX27. Down's syndrome causes overexpression of miR-155, a chromosome 21-encoded microRNA that negatively regulates C/EBPß, thereby reducing SNX27 expression and resulting in synaptic dysfunction. Upregulating SNX27 in the hippocampus of Down's syndrome mice rescues synaptic and cognitive deficits. Our identification of the role of SNX27 in synaptic function establishes a new molecular mechanism of Down's syndrome pathogenesis.