A Diet High in Saturated Fat and Sucrose Increases Susceptibility to Aspects of Alzheimer’s Disease in Aging Mice

Abstract

Alzheimer’s disease (AD) is a progressive, degenerative disorder of the brain and is the most common form of dementia in older adults. Prominent behavioral manifestations of AD include memory impairments and decline in other cognitive and non-cognitive domains. Clinical data suggest that the pathophysiological processes of AD begin more than a decade prior to the diagnosis of dementia. Therefore, in addition to increasing age, other factors could impose significant risks for developing AD. Diets rich in saturated fats and sugar (HFS) have been implicated in increasing risks for age-related diseases including AD but studies linking AD to HFS diets have been limited and at times controversial. A model of AAV vector (Aβ42 and pTau) mediated early stage AD in aging C57BL/6 mice was used to determine the impact of a HFS diet on the development of AD-associated cognitive impairment and neuropathology. Mice were started on the HFS diet and administered AAV-AD vectors intravenously at 20 months of age and followed for three months when they were tested for cognitive and non-cognitive behavior, white blood cell counts, and physical performance. Mice were then euthanized, and tissues collected for immunohistochemistry. The HFS diet generally increased cognitive impairment, anxiety, and incoordination and decreased strength in mice with AAV-AD in a sex-dependent manner. Neuronal Aβ42 showed increased density in the presence of AAV-AD and in association with decreased density of microglia and astrocytes. In conclusion, observations from this project suggest that behavioral and performance phenotypes may be associated with AD neuropathology but in a diet and sex dependent manner. The HFS diet is suspected of increasing neuronal susceptibility to AAV-AD in aging C57BL/6 mice, especially females, suggesting that a metabolically stressful diet could potentially increase the risk for neurodegeneration and development of cognitive decline and behavioral dysfunction.