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Thesis Format

Integrated Article


Doctor of Philosophy


Anatomy and Cell Biology


Cechetto, David F.


Metabolic syndrome (MetS), the development of which is associated with high-caloric Western diet intake, represents a risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD) and appears to contribute to AD progression when MetS and AD are comorbid. The interaction between AD and MetS might be through white matter inflammation, since white matter abnormalities and inflammation are important early events in the etiopathogenesis of both diseases. In these investigations, the effect of a high-caloric diet (HCD), to induce metabolic disturbances, on white matter neuroinflammation and cognitive function was investigated in a transgenic (TG) rat model of prodromal AD and MCI (APP21 TG). Rats maintained on the HCD developed obesity, dyslipidemia, hyperinsulinemia and glucose intolerance, but not hypertension. HCD-driven metabolic perturbations significantly exacerbated white matter microglia, but not astrocyte, activation in the TG rats. There were significant deficits in spatial reference memory in the comorbid TG HCD group compared to wildtype control rats. There were no changes in hippocampal neuronal or synaptic density in the comorbid group. In addition, single-regimen chronic prophylactic treatment with a novel brain-targeted NSAID prodrug Ketoprofen-lysine was not able to decrease the activation of white matter microglia and alleviate cognitive deficits in the comorbid model. In fact, the prodrug treatment alone was associated with two deaths and widespread neuroinflammation and neurodegeneration in a subset of rats further associated with a spatial working memory decline and cognitive inflexibility. Finally, white matter microglia activation was positively associated with visceral fat deposition and with transgene presence. Dyslipidemia was related to the greater white matter inflammation in the entire rat sample, however, showed an unexpected inverse association in the comorbid model. Thus, the APP21 TG rat combined with the HCD represents a good model for future studies on prodromal AD pathology and MetS. It can be used to study related cognitive dysfunction including effects of various comorbidities on the disease presentation, as well as provide a platform for testing treatment strategies and biomarker identification. The results support an important role of white matter inflammation in the interaction between prodromal AD and MetS and as a contributor to cognitive impairment.

Summary for Lay Audience

Alzheimer's disease (AD) is a highly prevalent and incurable brain disease in the elderly resulting in difficulty in thinking and communicating and memory loss. Metabolic syndrome (MetS), is another common disease in the elderly, largely due to the consumption of a hypercaloric Western diet high in fat and sugar. MetS represents a modifiable risk factor for AD. It can coexist with and likely interacts with AD, contributing to cognitive impairment. Investigating the pathological links between AD, especially at the very early stage, and MetS will advance our understanding of early disease processes, highlight therapeutic targets for early intervention and prevention, and identify markers of prodromal AD to aid early diagnosis and timely treatment. White matter abnormalities in brain are associated with cognitive dysfunction and inflammation and are important features of the initial stage of AD and MetS. Inflammation occurring in the white matter could be the basis of the interaction between AD and MetS. The studies in this thesis examined the contribution of a high-caloric (HCD)-induced MetS to the early AD pathology and changes in cognitive function using a novel genetically engineered rat carrying a human protein implicated in human AD. The combined model of AD predisposition and MetS demonstrated greater white matter inflammation which was caused by microglia (resident brain immune cells) and resulted in memory impairment. A novel brain-targeted chronic prophylactic anti-inflammatory treatment was not able to disrupt the detrimental interaction of early AD and MetS on white matter inflammation and to preserve cognitive function. However, serious neurological side effects were observed in several rats on the treatment. Accumulation of fat around the internal organs and blood lipid abnormalities were identified as potential biomarkers of increased white matter inflammation. However, abnormal blood lipids were associated with lower white matter inflammation in the combination of the early AD and MetS in the rats. In conclusion, the findings support the suggestion that white matter inflammation is a link between early AD and MetS. This rat model, closely mimicking human pathological conditions, represents a good platform for future studies on the complex relationships between AD and comorbidities, therapeutic approaches and biomarkers.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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