Regional differences in Alzheimer's disease pathology confound behavioural rescue after amyloid-β attenuation

Failure Alzheimer's disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer's disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal toss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-beta peptide in disease-bearing TgF344-AD) rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-beta peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in Vito electrophysiological signature of the hippocampus. Amyloid-beta peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neuro-genesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma hands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-beta peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation, Thus, rescue or nor of cognitive function is dependent on regional differences of amyloid-beta, tau and neuronal network dysfunction, demonstrating die importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.