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Establishment of Novel Murine Model showing Vascular Inflammation-derived Cognitive Dysfunction.

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.

SUBMITTER: Hashizume T

PROVIDER: S-EPMC6411753 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Establishment of Novel Murine Model showing Vascular Inflammation-derived Cognitive Dysfunction.

Hashizume Tsuyoshi T Son Bo-Kyung BK Taniguchi Sakiko S Ito Koichi K Noda Yoshihiro Y Endo Tamao T Nanao-Hamai Michiko M Ogawa Sumito S Akishita Masahiro M

Scientific reports 20190311 1

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 c ...[more]

PMID: 30858535

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Project description:BackgroundCachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx-Cre+/+ (KPC) mouse.MethodsMale and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development.ResultsAll routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone.ConclusionsSyngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

Dataset Information

Establishment of Novel Murine Model showing Vascular Inflammation-derived Cognitive Dysfunction.

Publications

Establishment of Novel Murine Model showing Vascular Inflammation-derived Cognitive Dysfunction.

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