The online version of this article (https://doi.org/10.1186/s12974-018-1059-y) contains supplementary material, which is available to authorized users.
Microglia function is essential to maintain the brain homeostasis. Evidence shows that aged microglia are primed and show exaggerated response to acute inflammatory challenge. Systemic inflammation signals to the brain inducing changes that impact cognitive function. However, the mechanisms involved in age-related cognitive decline associated to episodic systemic inflammation are not completely understood. The aim of this study was to identify neuropathological features associated to age-related cognitive decline in a mouse model of episodic systemic inflammation.
Young and aged Swiss mice were injected with low doses of LPS once a week for 6 weeks to induce episodic systemic inflammation. Sickness behavior, inflammatory markers, and neuroinflammation were assessed in different phases of systemic inflammation in young and aged mice. Behavior was evaluated long term after episodic systemic inflammation by open field, forced swimming, object recognition, and water maze tests.
Episodic systemic inflammation induced systemic inflammation and sickness behavior mainly in aged mice. Systemic inflammation induced depressive-like behavior in both young and aged mice. Memory and learning were significantly affected in aged mice that presented lower exploratory activity and deficits in episodic and spatial memories, compared to aged controls and to young after episodic systemic inflammation. Systemic inflammation induced acute microglia activation in young mice that returned to base levels long term after episodic systemic inflammation. Aged mice presented dystrophic microglia in the hippocampus and entorhinal cortex at basal level and did not change morphology in the acute response to SI. Regardless of their dystrophic microglia, aged mice produced higher levels of pro-inflammatory (IL-1β and IL-6) as well as pro-resolution (IL-10 and IL-4) cytokines in the brain. Also, higher levels of Nox2 expression, oxidized proteins and lower antioxidant defenses were found in the aged brains compared to the young after episodic systemic inflammation.
Our data show that aged mice have increased susceptibility to episodic systemic inflammation. Aged mice that showed cognitive impairments also presented higher oxidative stress and abnormal production of cytokines in their brains. These results indicate that a neuroinflammation and oxidative stress are pathophysiological mechanisms of age-related cognitive impairments.
Additional file 1: Figure S1. Photomicrographs of senescence marker lipofuscin present in the aged brains only. Brain sections without any treatment incubated with mounting media for fluorescence (Vectashield), observed under fluorescence microscope show the tissue autofluorescence in the cortex of the aged mice. It is possible to observe the auto fluorescent aggregates in both the green (A) and the red (B) channels. Scale bar: 20 μm. (DOCX 3481 kb)12974_2018_1059_MOESM1_ESM.docx
Additional file 2: Figure S2. Blood cytokines acutely after the first LPS injection. Blood cytokines were measured 4 h and 7 days after the first LPS injection. A) Blood IL-1β was significantly increased in aged mice 7 days after LPS. B) Blood IL-6 was less upregulated in aged mice 4 h after LPS injection. C) Blood IL-10 levels were not altered acutely. D) Blood IL-4 was significantly decreased in aged mice 7 days after LPS injection. Two-way ANOVA with Bonferroni posttest (*p < 0.05) and t test (#p < 0.05). (DOCX 192 kb)12974_2018_1059_MOESM2_ESM.docx
Additional file 3: Figure S3. Blood cytokines long term after chronic low-grade systemic inflammation. Blood cytokines IL-1β (A), IL-6 (B), IL-4 (C), and IL-10 (D) were measured in young and aged mice naïve (control) and after chronic low-grade systemic inflammation (CSI). IL-4 levels remained significantly decreased in the blood of aged mice after CSI (*p < 0.05). (DOCX 96 kb)12974_2018_1059_MOESM3_ESM.docx
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- Age-related cognitive impairment is associated with long-term neuroinflammation and oxidative stress in a mouse model of episodic systemic inflammation
Joana Costa d’Avila
Luciana Domett Siqueira
Estefania Pereira Azevedo
Hugo Caire Castro-Faria-Neto
Fernando Augusto Bozza
- BioMed Central