Modeling AD‐related metabolic impairments in the TgF344‐AD rat model

Abstract

AbstractBackgroundAlzheimer’s disease (AD) not only affects cognition and neuropathology, but has several other facets capable of negatively impacting quality of life, including impaired metabolic function, which is present in ∼80% of cases. However, the influence of metabolism is seldom considered when utilizing rodent models of AD, particularly in conjunction with cognitive impairment and neuropathology. Therefore, we characterized metabolic and cognitive status of the TgF344‐AD rat model first presented in Cohen et al. in 2013.MethodAged (20‐26 mo) female rats were utilized. Metabolic health was characterized through body composition analysis, food consumption quantification, insulin and glucose tolerance tests and hypothalamic p‐AKT/AKT response to insulin. Cognition was assessed through object discrimination tasks, including novel object discrimination, working memory/object discrimination and working memory/biconditional association tasks. This series of increasingly complex behavioral tasks requires proper function of individual brain regions, as well as integration of information across these regions, in which AD‐related pathology is commonly observed.ResultAD rats required significantly more trials before reaching criterion performance across several tasks, including a working memory/object recognition task and a working memory/biconditional association task. However, there were no group differences in ability to perform a simple object discrimination, demonstrating all rats were able to participate procedurally, therefore differences in performance can be attributed to cognitive impairment. AD rats had significantly more body fat than WT, and lost significantly less weight than their wild type (WT) counterparts while relocating to our colony, despite consistent food consumption across groups. Moreover, glucose appears to be rapidly degraded in AD rats relative to WT controls, indicating significant differences in metabolic function across genotypes.ConclusionTogether, these data indicate that not only do we observe genotype‐specific deficits in cognitive function, but also that the transgenic rats metabolize their energy sources in different ways than WT littermates. The long range projection neurons required to support task acquisition are more metabolically costly than locally projecting neurons, and thus most likely affected by the impaired metabolic function in this rats. Therefore, treatments targeting these metabolic deficits may help prevent or ameliorate AD‐related cognitive decline.