TgF344-AD Rat Model of Alzheimer’s Disease: Spatial Disorientation and Asymmetry in Hemispheric Neurodegeneration

Abstract

Background: The TgF344-AD ratline represents a transgenic animal model of Alzheimer’s disease. We previously reported spatial memory impairment in TgF344-AD rats, yet the underlying mechanism remained unknown. We, therefore, set out to determine if spatial memory impairment in TgF344-AD rats is attributed to spatial disorientation. Also, we aimed to investigate whether TgF344-AD rats exhibit signs of asymmetry in hemispheric neurodegeneration, similar to what is reported in spatially disoriented AD patients. Finally, we sought to examine how spatial disorientation correlates with working memory performance. Methods: TgF344-AD rats were divided into two groups balanced by sex and genotype. The first group underwent the delayed match-to-sample (DMS) task for the assessment of spatial orientation and working memory, while the second group underwent positron emission tomography (PET) for the assessment of glucose metabolism and microglial activity as in-vivo markers of neurodegeneration. Rats were 13 months old during DMS training and 14–16 months old during DMS testing and PET. Results: In the DMS task, TgF344-AD rats were more likely than their wild-type littermates to display strong preference for one of the two levers, preventing working memory testing. Rats without lever-preference showed similar working memory, regardless of their genotype. PET revealed hemispherically asymmetric clusters of increased microglial activity and altered glucose metabolism in TgF344-AD rats. Conclusions: TgF344-AD rats display spatial disorientation and hemispherically asymmetrical neurodegeneration, suggesting a potential causal relationship consistent with past clinical research. In rats with preserved spatial orientation, working memory remains intact.

Adolescent alcohol exposure alters age-related progression of behavioral and neurotrophic dysfunction in the TgF344-AD model in a sex-specific manner

“…Another study found that TgF344-AD rats develop strong preference for one of the two levers, that prevented memory assessment with DMTP in 50% of rats (Sagalajev et al, 2023). In AD-rats that did not develop lever-preferences, and no spatial short-term memory impairments were observed on either DMTP (Sagalajev et al, 2023) or DNMTP (Muñoz-Moreno et al, 2018). Those studies did not include sex as a factor, which we show can influence this behavioral assay.…”

“…In contrast, the opposite effect was found in male rats: AIE and AD transgenes improved short-term memory performance. Another study found that TgF344-AD rats develop strong preference for one of the two levers, that prevented memory assessment with DMTP in 50% of rats (Sagalajev et al, 2023). In AD-rats that did not develop lever-preferences, and no spatial short-term memory impairments were observed on either DMTP (Sagalajev et al, 2023) or DNMTP (Muñoz-Moreno et al, 2018).…”