Abstract
BackgroundAβ1-42 peptide abnormal production is associated with the development and maintenance of neuroinflammation and oxidative stress in brains from Alzheimer disease (AD) patients. Suppression of neuroinflammation may then represent a suitable therapeutic target in AD. We evaluated the efficacy of IFNβ1a in attenuating cognitive impairment and inflammation in an animal model of AD.MethodsA rat model of AD was obtained by intra-hippocampal injection of Aβ1-42 peptide (23 μg/2 μl). After 6 days, 3.6 μg of IFNβ1a was given subcutaneously (s.c.) for 12 days. Using the novel object recognition (NOR) test, we evaluated changes in cognitive function. Measurement of pro-inflammatory or anti-inflammatory cytokines, reactive oxygen species (ROS), and SOD activity levels was performed in the hippocampus. Data were evaluated by one-way ANOVA with Fisher’s Protected Least Significant Difference (PLSD) test.ResultsWe showed that treatment with IFNβ1a was able to reverse memory impairment and to counteract microglia activation and upregulation of pro-inflammatory cytokines (IL-6, IL-1β) in the hippocampus of Aβ1-42-injected rats. The anti-inflammatory cytokine IL-10, significantly reduced in the Aβ1-42 animals, recovered to control levels following IFNβ1a treatment. IFNβ1a also reduced ROS and lipids peroxidation and increased SOD1 protein levels in the hippocampus of Aβ1-42-injected rats.ConclusionThis study shows that IFNβ1a is able to reverse the inflammatory and cognitive effects of intra-hippocampal Aβ1-42 in the rat. Given the role played by inflammation in AD pathogenesis and the established efficacy of IFNβ1a in the treatment of inflammatory diseases of the central nervous system such as multiple sclerosis, its use may be a viable strategy to inhibit the pro-inflammatory cytokine and oxidative stress cascade associated with Aβ deposition in the hippocampus of AD patients.
Highlights
Amyloid β Protein Fragment 1-42 (Aβ1-42) peptide abnormal production is associated with the development and maintenance of neuroinflammation and oxidative stress in brains from Alzheimer disease (AD) patients
We preliminarily evaluated the safety and efficacy of IFNβ1a in subjects affected by mild-to-moderate AD in a phase 2a study mainly aimed to evaluate the safety of the drug in this elderly population [24], and not statistically significant, we observed a reduction in disease progression during follow-up as measured by the AD Physical Self-Maintenance Scale
The scheme of dose and time of IFNβ1a treatment was based on previous work using a similar experimental rat model [20] or a rat model of autoimmune encephalomyelitis [40,41,42]
Summary
Aβ1-42 peptide abnormal production is associated with the development and maintenance of neuroinflammation and oxidative stress in brains from Alzheimer disease (AD) patients. All anti-inflammatory strategies tried so far in AD patients have not achieved satisfactory results, indicating the need for a better understanding of the role of the immune system in cerebral proteinopathies and how to modulate it [10], intervention with drugs modulating pro-inflammatory cytokine production is still considered a potentially useful strategy to slow down the disease course of this dreadful disease. Interferon-β1a (IFNβ1a) is the prototypical regulatory cytokine with anti-inflammatory properties largely used in the past two decades to slow down pathological and clinical features of central nervous system (CNS) immune-mediated diseases, such as multiple sclerosis [12,13,14,15,16,17] and its animal model experimental autoimmune encephalomyelitis [18, 19]. We preliminarily evaluated the safety and efficacy of IFNβ1a in subjects affected by mild-to-moderate AD in a phase 2a study mainly aimed to evaluate the safety of the drug in this elderly population [24], and not statistically significant, we observed a reduction in disease progression during follow-up as measured by the AD Physical Self-Maintenance Scale
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