All ETDs from UAB

Advisory Committee Chair

Lori L McMahon

Advisory Committee Members

Lynn E Dobrunz

Karen L Gamble

Erik D Roberson

Inga Kadish

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Alzheimer’s disease (AD) is the leading cause of dementia in those 65 years and older and the 6th leading cause of death in the United Sates. Current treatments only target symptoms of the disease and cannot slow or halt disease progression. The novel and comprehensive TgF344-AD rodent model may bridge the translational gap previous animal models have failed to traverse by providing the platform to probe pre-lesion synapse dysfunction, which is thought to result primarily from increased levels of toxic soluble amyloid beta and hyperphosphorylated tau. The most recently developed model, the TgF344-AD rat was created in 2013 by insertion of the human APPSwe and PS1ΔE9 early onset Alzheimer’s disease (EOAD) transgenes driven by the mouse prion promoter on the Fischer 344 rat background (Cohen et al., 2013). Previous mouse and rat models of AD are criticized in that they fail to develop tau tangles or neuronal loss, both prominent pathological features in human AD. Fortunately, this model is the most comprehensive preclinical rodent model of AD to-date, as it faithfully recapitulates core AD-like pathologies in an age-dependent manner (i.e. increased soluble amyloid beta oligomers (Abo) and hyperphosphorylated tau species, gliosis, cognitive impairments on memory tasks, amyloid plaques, tau tangles, and neuronal loss). The studies outlined in this dissertation are the first to assess longitudinal synapse-specific and sex-specific synaptic changes in acute hippocampal slices from TgF344-AD rats. Results from these studies show the spatiotemporal spread of presymptomatic synapse dysfunction begins earlier than expected, at 6 months of age, and mimics the spread of synapse dysfunction thought to occur in human hippocampus by targeting the dentate gyrus prior to area CA1. In addition, basal synaptic strength is decreased as early as 6 months in dentate gyrus and occurs months before area CA1. The decrease in synaptic strength is delayed in females compared to males supporting a neuroprotective effect of ovarian hormones. Further, presynaptic release probability was not altered and suggests a postsynaptic mechanism for decreased synaptic strength. Long-term potentiation (LTP) was pathologically increased in TgF344-AD dentate at 6 months. Additional whole-cell electrophysiology experiments determined that dentate granule cell excitability is increased by 6 months and may provide a mechanistic explanation for enhanced LTP at this age. Sex differences are well documented in human AD and these longitudinal studies from the TgF344-AD rat model support there are sex differences in synaptic function as pathology progresses between males and females. Overall, these findings are the first to recapitulate the patterned spread of synapse dysfunction and early excitatory/inhibitory imbalance reported in human AD in the TgF344-AD rat model. Together these data provide the first synaptic evidence that support the TgF344-AD rat model as a novel preclinical tool for investigating the earliest pathological changes in AD brain.



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