Student Theses and Dissertations
The Effect of Early Dietary Intervention on Alzheimer's Disease-Related Pathology and Cognitive Function in Mice
Date of Award
Doctor of Philosophy (PhD)
Alzheimer’s disease (AD) is a fatal cognitive disorder with proteinaceous brain deposits, neuroinflammation, cerebrovascular dysfunction, and extensive neuronal loss. AD is a multifactorial disease, and lifestyle factors, including diet, are likely associated with the development of AD pathology. Since obesity and diabetes are recognized as risk factors for AD, it might be predicted that a high fat diet (HFD) would worsen AD pathology. However, modeling HFD-induced obesity in animal models of AD has yielded inconclusive results. Some studies report a deleterious effect of HFD on Aβ accumulation, neuroinflammation, and cognitive function, while others report that HFD worsens memory without affecting AD brain pathology. Moreover, several studies report no major effect of HFD on AD-related phenotypes in mice, while other studies show that HFD might, in fact, be protective. The lack of a clear association between HFD consumption and AD-related pathology and cognitive function in AD mouse models might be explained by experimental variations, including AD mouse model, sex of the animals, composition of the HFD, and timeline of HFD consumption. Our study examined the effect of varying the timeline of HFD or control diet (CON) consumption on AD-related pathology and cognitive function in transgenic Tg6799 AD mice. HFD consumption that started at or before 3 months-of-age, prior to severe AD pathology, had protective effects in AD mice. Specifically, it reduced extracellular beta-amyloid (Aβ) deposition, decreased fibrinogen extravasation from blood vessels into the brain parenchyma, and improved cognitive function. RNAseq analysis revealed that HFD affected the expression of genes in the AD mouse cortex related to the stress response, protein folding, endoplasmic reticulum stress, chaperone-mediated protein folding, and the immune system process in AD mice. However, delaying HFD consumption until 6 months-ofage, when AD pathology is ubiquitous, did not provide neuroprotection in AD mice, as there was no change in cortical Aβ deposition in 11-month-old mice. Surprisingly, despite the delayed onset of HFD consumption, HFD still reduced the extravasation of fibrinogen into the brain. Overall, we demonstrate that the timeline of HFD consumption plays an important role in how dietary fats affect AD-related pathology and cognitive function in a transgenic mouse model of AD.
Amelianchik, Anna, "The Effect of Early Dietary Intervention on Alzheimer's Disease-Related Pathology and Cognitive Function in Mice" (2022). Student Theses and Dissertations. 666.
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy