Disruption of electrophysiological rhythms and memory impairment in an Alzheimer's transgenic rat model

Alzheimer's disease (AD) is one of the most prevalent causes of dementia, characterized by progressive memory loss and cognitive decline. Abnormal electrophysiological patterns, especially interictal epileptiform discharges (IEDs) and high-frequency oscillations (HFOs), have been observed in mouse models of AD and are suggested to contribute to cognitive dysfunction. However, comprehensive evaluations of IEDs across different brain regions are limited, and their impact on cognitive performance and neuropathology remains unclear, particularly in more complex AD models with relevant comorbidities. To address this gap, our study aims to clarify how IEDs and HFOs contribute to cognitive decline and neuropathology in AD, potentially informing the development of new biomarkers for early detection.

We investigate these effects in an AD (PS1/APP) rat model (FAD+) with coexisting hypertension-associated small vessel disease (SVD), as well as in their transgene-negative littermates (FAD-). We conducted behavioral experiments at 6, 8, and 11 months of animal age, alongside neural signal recordings at 8 and 11 months. AD pathology (neuritic plaques and hyperphosphorylated tau) and novel biomarkers (14-3-3γ) or biomarkers common to both disorders (neuropeptide Y, astrocyte and microglia) were evaluated at the end of the experiment.

Seizures were observed in three out of 14 FAD + rats. IED rates were significantly greater in FAD + rats compared to FAD- at all tested periods, correlating with changes in neuropathological biomarkers. Furthermore, coupling strength between IEDs and HFOs was significantly elevated in FAD + rats, especially during the later stages of disease progression. In addition, FAD + rats exhibited deficits in both learning and recall abilities at both ages, which correlated most strongly with increased IED-HFO coupling strength. No such correlation was observed in the FAD- group.

Our findings suggest that pathological synchronization between IEDs and HFOs in the hippocampus, along with neuropathological changes in both the hippocampus and entorhinal cortex, may contribute to memory dysfunction in AD, highlighting a potential mechanistic link between epileptiform activity, AD biomarker changes, and cognitive decline.