Cognitive decline and neuroinflammation in a mouse model of obesity: An accelerating role of ageing

Obesity, a pandemic, worldwide afflicts almost one billion people. Obesity and ageing share several pathological pathways leading to neurological disorders. However, due to a lack of suitable animal models, the long-term effects of obesity on age-related disorders- cognitive impairment and dementia have not yet been thoroughly investigated. Therefore, the current investigation focuses on developing a suitable model to explore the effects of obese-ageing. It also aims to determine whether obesity affects cognitive abilities in an age-dependent manner, and to identify a potential biomarker(s) for cognitive decline. Cognitive tests were carried out on 6-months and 1-year-old melanocortin-4 receptor (Mc4r)-deficient-obese and lean (wildtype) mice. Additionally, brains and sera were harvested for molecular, histological and serological analyses from 6, 12, and 24-months-old mice. Finally, RT-PCR was carried out after hippocampal mRNA sequencing. The cognitive tests revealed that 1-year-old obese mice have cognitive impairment along with underlying neurodegenerative changes, such as enlarged lateral ventricles. Serum neurofilament light chain (sNfL) levels were also elevated. Lipid accumulation and neuroinflammation were apparent besides, a compromised blood-brain barrier (BBB) indicated by altered junction protein gene expression. Differentially-expressed genes associated with cognitive decline were identified by mRNA sequencing of hippocampi. One such gene, Secreted Phosphoprotein 1 (Spp1) had markedly increased expression in cognitively-impaired obese mice. Our findings present an obese-aged mouse model of cognitive decline with neuroinflammation, reduced BBB-integrity and predisposing neurodegenerative changes. Obese-ageing accelerates the progression of cognitive impairment. Furthermore, Spp1 appears to be a potential biomarker for early diagnosis of neuropathological disorders.