RESUMEN
Interferon beta (IFNß) is a member of the type-1 interferon family and has various immunomodulatory functions in neuropathological conditions. Although the level of IFNß is low under healthy conditions, it is increased during inflammatory processes to protect the central nervous system (CNS). In particular, microglia and astrocytes are the main sources of IFNß upon inflammatory insult in the CNS. The protective effects of IFNß are well characterized in reducing the progression of multiple sclerosis (MS); however, little is understood about its effects in other neurological/neurodegenerative diseases. In this review, different types of IFNs and their signaling pathways will be described. Then we will focus on the potential role and therapeutic effect of IFNß in several CNS-related diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury, prion disease and spinocerebellar ataxia 7.
Asunto(s)
Interferón beta , Humanos , Animales , Interferón beta/uso terapéutico , Interferón beta/metabolismo , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Alzheimer's disease (AD) patients frequently experience neuropsychiatric symptoms (NPS), which are linked to a lower quality of life and a faster rate of disease progression. A growing body of research indicates that several microglial phenotypes control the inflammatory response and are crucial in the pathophysiology of AD-related NPS. Given the crucial role played by inflammatory mediators produced by microglia in developing of NPS, interferon-beta (IFNß), a cytokine with anti-inflammatory capabilities, maybe a successful treatment for NPS caused by AD. In this investigation, using a rat model of AD, we examined the impact of intranasal treatment of IFNß on anxious/depressive-like behavior and microglial M1/M2 polarization. The rat hippocampus was bilaterally injected with lentiviruses harboring mutant human amyloid precursor protein. Rats were given recombinant IFNß1a (68,000 IU/rat) via the intranasal route, starting on day 23 following viral infection and continuing until day 49. On days 47-49, the elevated plus maze, forced swim, and tail suspension tests were applied to measure anxiety- and depressive-like behavior. Additionally, qPCR was utilized to quantify the expression of M1 markers (CD68, CD86, and CD40) and M2 markers (Ym1, CD206, Arg1, GDNF, BDNF, and SOCS1). Our findings demonstrated that decreased M2 marker expression is accompanied by anxious/depressive-like behavior when the mutant human APP gene is overexpressed in the hippocampus. In the rat model of AD, IFNß therapy reduces anxious/depressive-like behaviors, at least in part by polarizing microglia towards M2. Therefore, IFNß may be a viable therapeutic drug for reducing NPS in the context of AD.
Asunto(s)
Enfermedad de Alzheimer , Microglía , Animales , Humanos , Ratas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Ansiedad/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Interferón beta , Microglía/metabolismo , Calidad de Vida , Depresión/tratamiento farmacológicoRESUMEN
Interferon beta (IFNß) is a cytokine with anti-apoptotic and anti-inflammatory properties, and its beneficial effects on Alzheimer's disease (AD) have been recently shown. The alterations in cerebral glucose uptake are closely linked to memory deficit and AD progression. The current study was designed to determine if IFNß can improve recognition memory and brain glucose uptake in a rat model of AD. The lentiviruses expressing mutant human amyloid precursor protein were injected bilaterally to the rat hippocampus. From day 23 after virus injection, rats were intranasally treated with recombinant IFNß protein (68,000 IU/rat) every other day until day 50. Recognition memory performance was evaluated by novel object recognition test on days 46-49. The 18F-2- fluoro-deoxy-d-glucose positron emission tomography (18F-FDG-PET) was used to determine changes in brain glucose metabolism on day 50. The expression of the PI3K/Akt pathway components, neurotrophins and mitochondrial biogenesis factors were also measured by qPCR in the hippocampus. Our results showed that IFNß treatment improves recognition memory performance in parallel with increased glucose uptake and neuronal survival in the hippocampus of the AD rats. The neuroprotective effect of IFNß could be attributed, at least partly, to activation of PI3K-Akt-mTOR signaling pathway, increased expression of NGF, and mitochondrial biogenesis. Taken together, our findings suggest the therapeutic potential of IFNß for AD.