RESUMO
Current therapies for Alzheimer's disease (AD) are symptomatic and do not target the underlying Aß pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of ß-APP cleaving enzyme (BACE1), the main enzyme involved in Aß generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aß deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aß pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.
Assuntos
Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Ácido Aspártico Endopeptidases/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Agregação Patológica de Proteínas/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Animais , Regulação da Expressão Gênica/genética , Vetores Genéticos/uso terapêutico , Humanos , Lentivirus/genética , Memória/fisiologia , Camundongos Transgênicos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/administração & dosagem , Agregação Patológica de Proteínas/terapia , Células Piramidais/metabolismo , Células Piramidais/patologiaRESUMO
The receptor interacting protein-140 (RIP140) is a cofactor for several nuclear receptors and has been involved in the regulation of metabolic and inflammatory genes. We hypothesize that RIP140 may also affect Aß generation because it modulates the activity of transcription factors previously implicated in amyloid precursor protein (APP) processing, such as peroxisome proliferator-activated receptor-γ (PPARγ). We found that the levels of RIP140 are reduced in Alzheimer's disease (AD) postmortem brains compared with healthy controls. In addition, in situ hybridization experiments revealed that RIP140 expression is enriched in the same brain areas involved in AD pathology, such as cortex and hippocampus. Furthermore, we provide evidence using cell lines and genetically modified mice that RIP140 is able to modulate the transcription of certain genes involved in AD pathology, such as ß-APP cleaving enzyme (BACE1) and GSK3. Consequently, we found that RIP140 overexpression reduced the generation of Aß in a neuroblastoma cell line by decreasing the transcription of ß-APP cleaving enzyme via a PPARγ-dependent mechanism. The results of this study therefore provide molecular insights into common signaling pathways linking metabolic disease with AD.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Expressão Gênica/genética , Proteínas Nucleares/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Secretases da Proteína Precursora do Amiloide , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases , Encéfalo/metabolismo , Células Cultivadas , Feminino , Quinase 3 da Glicogênio Sintase , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Proteína 1 de Interação com Receptor Nuclear , PPAR gama/metabolismo , Transdução de Sinais , Transcrição Gênica/genéticaRESUMO
Peroxisome proliferator-activated receptor-γ (PPARγ) was initially involved in the regulation of glucose and lipid metabolism, cell differentiation, as well as in the transcriptional control of a wide range of inflammatory genes. However, during the last decade, there has been evidence of the implication of this nuclear receptor in neurodegeneration. Various studies have shown that the administration of PPARγ ligands leads to a reduced pathology in many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, and stroke. PPARγ cofactors have a critical function in regulating the activity of PPARγ. Recent reports have brought to light the role of the PPARγ coactivator-1α (PGC-1α) in several neurodegenerative pathologies. However, very little is know about other PPARγ cofactors in the brain, such as the receptor-interacting protein 140, as well as the nuclear receptor corepressor, which seems to be required for normal neural development at specific embryonic stages. In this review, we aim to analyze the role of the main regulators of PPARγ in the brain and during neurodegeneration.
