Heightened β-adrenergic receptor function in the novel TgF344-AD rat drives hippocampal learning and memory in prodromal Alzheimer's Disease
There are currently no effective treatments for Alzheimer’s Disease (AD). Understanding the early pathogenesis of AD is vital for future development of treatment. Prodromal AD refers to the earliest phases of disease, where amyloid-beta (Aβ) plaques and hyperphosphorylated tau (pTau) begin to accumulate with no apparent cognitive deficits. Previous animal models have failed to express prodromal AD pathology. The novel TgF344-AD rat model recapitulates prodromal human AD pathology with pTau expression. How this preclinical model and human AD lack a behavioral deficit when AD pathology begins buildup in the brain is unclear. Recent demonstration of heightened long-term potentiation (LTP) of β-adrenergic receptors (βARs) at dentate gyrus synapses in TgF344-AD rats provides a possible mechanism for maintenance of learning and memory behavior. In this study, we sought to test the hypothesis that TgF344-AD rats rely more heavily on βARs in hippocampal-dependent learning and memory compared to WT rats, providing a possible mechanism for prodromal AD. We blocked βAR function in novel object recognition (NOR) and fear extinction learning tasks, to test whether a behavioral deficit would be unmasked in AD animals. Our data reveals that βARs are required for successful fear extinction learning in TgF344-AD rats and not in WT rats, and that TgF344-AD rats have a behavioral advantage requiring βARs over WT rats in NOR learning and memory. This indicates a greater reliance on βARs, suggesting the increase in βAR function during prodromal AD in TgF344-AD rats acts as a compensatory mechanism to preserve some forms of learning and memory.