| dc.description.abstracteng | Genetic or lifestyle-related obesity ails almost one billion people worldwide. Obesity is an accumulation of fat, while, ageing is an ongoing process of accumulation of harmful molecular alterations. Obesity and ageing, independently, contribute to the pathology of neurodegenerative diseases. Interestingly, with co-progression they enhance each other and accelerate the onset of diseases. Usually, neurodegenerative diseases appear in late-age and revealing ongoing irreversible damage in the CNS. Therefore, in this project, I sought to investigate the consequences of obese-ageing on cognitive decline and deduce an early candidate biomarker of cognitive decline.
In this study, I analysed the cognitive abilities of Mc4r-deficient obese mice aged 6-9 months (here referred to as 6-months-old) and 12-15 months (here referred to as 1-year-old) using a battery of behaviour tests. Open field, novel object recognition, and water-maze test were performed, to gauge the cognitive abilities of the obese mice vs. lean litter-mates. Following behaviour tests, molecular, and immuno-histological analyses were performed, with brain samples harvested from all cohorts. Additionally, immuno-assays were performed for serological analyses.
1-year-old obese mice showed a behavioral phenotype of cognitive deficit. Subsequent macroscopic and microscopic analyses indicated that obese mice harbour cerebral atrophy and therefore dilated lateral ventricles. Axonal damage was confirmed by analysing sera neurofilament light chain in the 1-year old obese mice. Further immunoassay of sera confirmed systemic inflammation in 6-month and 1-year-old obese mice.
Adipose hypertrophy and hyperplasia produces enhanced levels of pro-inflammatory factors causing chronic systemic inflammation. Systemic inflammation, in addition to the lipid influx through a leaky blood-brain-barrier, elicits an immune response in the brain. This neuroinflammation in the brain was confirmed by increased presence of microglia in the 1-year-old obese mice.
Furthermore, an mRNA sequencing profile of hippocampus of 1-year-old obese mice was procured. The transcriptional data revealed a number of differentially expressed genes that are suspected to play an important role in cognitive decline associated to obese-ageing. Secreted phosphoprotein 1 (Spp1) a.k.a. osteopontin, was screened as a potential early candidate biomarker of cognitive decline. Spp1 has an upregulated gene expression in the hippocampus of obese mice along with increased presence in the sera of obese mice.
Overall, my work suggests that obese-ageing accelerates the onset of cognitive decline with a likelihood to transform into neurodegeneration. Based on preliminary data, Spp1 appears to be a promising early cognitive decline marker. Therefore, further investigation of Spp1, including in humans, has the potential to offer an interesting prospect towards having a promising cognitive decline marker. | de |