RESUMEN
The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral Aß amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis-Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10-3), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10-5) and plasma tau concentration (0.06 log2(ng l-1) 95%CI 0.03; 0.08, p = 4.55 × 10-6). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.
Asunto(s)
Estudio de Asociación del Genoma Completo , Enfermedades Neurodegenerativas , Componente Amiloide P Sérico , Humanos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Componente Amiloide P Sérico/metabolismo , Componente Amiloide P Sérico/genética , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/etiología , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Análisis de la Aleatorización Mendeliana , Biomarcadores , Proteínas tau/metabolismo , Proteínas tau/genética , Enfermedad por Cuerpos de Lewy/genética , Enfermedad por Cuerpos de Lewy/metabolismo , Masculino , FemeninoRESUMEN
Serum amyloid P component (SAP) is a member the innate immune humoral arm and participated in various processes, including the innate immune responses, tissue remodeling, and the pathogenesis of inflammatory diseases. Remarkably, SAP is a highly versatile immunomodulatory factor that can serve as a drug target for treating amyloid diseases and reduce inflammation, fibrosis degree, and respiratory disease. In this review, we focus on the biological activities of SAP and its application in different systemic immune-associated diseases. First, we reviewed the regulatory effects of SAP on innate immune cells and possible mechanisms. Second, we emphasized SAP as a diagnostic marker and therapeutic target for immune-associated diseases, including the neuropsychiatric disorders. Third, we presented several recommendations for regulating SAP in immune cell function and potential areas for future research. Some authorities consider SAP to be a pattern recognition molecule that plays multiple roles in the innate immune system and inflammation. Developing therapeutics that target SAP or its associated signaling pathways may be a promising strategy for treating immune-associated diseases.
