Abstract
Inflammation is a critical feature of aging and its related diseases, including cardiovascular diseases. Recent epidemiological studies demonstrated that abdominal aortic aneurysm (AAA), an aging-related vascular pathological condition, is associated with cognitive decline. However, the underlying mechanism, especially the role of vascular inflammation, is largely unknown because of lack of an available animal model. In this study, we examined whether vascular inflammation affects synaptic and cognitive dysfunction, using an AAA mouse model. In young (3 months) and middle-aged (12 months) C57BL/6J mice, AAA was induced by angiotensin II infusion with calcium chloride application. After 4 weeks of induction, aortic diameter was significantly increased and excessive Mac3-positive inflammatory cells infiltrated the destroyed aorta in middle-aged mice. AAA-induced middle-aged mice further exhibited cognitive impairment. Neuronal loss was observed in the CA3 region of the hippocampus. IBA1/MHCII-double-positive microglia activation was also seen in the hippocampus, suggesting that vascular inflammation drives neuroinflammation and subsequent cognitive dysfunction. Furthermore, we found that senescence-accelerated mice prone 8 exhibited robust AAA formation and a marked decrease of cognitive and synaptic function in the hippocampus mediated by inflammation. In conclusion, this novel murine model convincingly suggested the occurrence of vascular inflammation-derived cognitive dysfunction.
Highlights
Www.nature.com/scientificreports inflammation has been suggested to contribute to this relationship between aging-related vascular pathology and cognitive decline[27], the effects of vascular inflammation on cognitive function have not been fully determined, due to lack of available animal models
The present study investigated whether vascular inflammation drives synaptic dysfunction and cognitive decline through neuroinflammation, using a newly established mouse model
Using an abdominal aortic aneurysm (AAA) model, we found that vascular inflammation drives cognitive dysfunction, and further found, mechanistically, that macrophage-mediated inflammation in the aorta leads to microglial activation in the hippocampus, which is likely to be the basis of synaptic and cognitive impairment
Summary
Www.nature.com/scientificreports inflammation has been suggested to contribute to this relationship between aging-related vascular pathology and cognitive decline[27], the effects of vascular inflammation on cognitive function have not been fully determined, due to lack of available animal models. After 4 weeks of AAA induction, increased diameter of the abdominal aorta was observed in 12-month-old (middle-aged, M) mice compared with 3-month-old (young, Y) mice. Infiltration of Mac3-positive inflammatory cells was seen in the aorta and IBA1/MHCII-double-positive microglia activation in the hippocampus of AAA-induced M mice, suggesting that vascular inflammation drives neuroinflammation and subsequent cognitive impairment. This novel murine model convincingly suggested the occurrence of vascular inflammation-derived cognitive dysfunction
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