RESUMO
In preclinical Alzheimer's disease (AD), spatial learning and memory is impaired. We reported similar impairments in 3xTg-AD mice on a virtual maze (VM) spatial-reorientation-task that requires using landmarks to navigate. Hippocampal (HPC)-cortical dysfunction during sleep (important for memory consolidation) is a potential mechanism for memory impairments in AD. We previously found deficits in HPC-cortical coordination during sleep coinciding with VM impairments the next day. Some forms of 40 Hz stimulation seem to clear AD pathology in mice, and improve functional connectivity in AD patients. Thus, we implanted a recording array targeting parietal cortex (PC) and HPC to assess HPC-PC coordination, and an optical fiber targeting HPC for 40 Hz or sham optogenetic stimulation in 3xTg/PV cre mice. We assessed PC delta waves (DW) and HPC sharp wave ripples (SWRs). In sham mice, SWR-DW cross-correlations were reduced, similar to 3xTg-AD mice. In 40 Hz mice, this phase-locking was rescued, as was performance on the VM. However, rescued HPC-PC coupling no longer predicted performance as in NonTg animals. Instead, DWs and SWRs independently predicted performance in 40 Hz mice. Thus, 40 Hz stimulation of HPC rescued functional interactions in the HPC-PC network, and rescued impairments in spatial navigation, but did not rescue the correlation between HPC-PC coordination during sleep and learning and memory. Together this pattern of results could inform AD treatment timing by suggesting that despite applying 40 Hz stimulation before significant tau and amyloid aggregation, pathophysiological processes led to brain changes that were not fully reversed even though cognition was recovered. Significance Statement: One of the earliest symptoms of Alzheimer's disease (AD) is getting lost in space or experiencing deficits in spatial navigation, which involve navigation computations as well as learning and memory. We investigated cross brain region interactions supporting memory formation as a potential causative factor of impaired spatial learning and memory in AD. To assess this relationship between AD pathophysiology, brain changes, and behavioral alterations, we used a targeted approach for clearing amyloid beta and tau to rescue functional interactions in the brain. This research strongly connects brain activity patterns during sleep to tau and amyloid accumulation, and will aid in understanding the mechanisms underlying cognitive dysfunction in AD. Furthermore, the results offer insight for improving early identification and treatment strategies.
RESUMO
In early Alzheimer's disease (AD) spatial navigation is one of the first impairments to emerge; however, the precise cause of this impairment is unclear. Previously, we showed that, in a mouse model of tau and amyloid beta (Aß) aggregation, getting lost represents, at least in part, a failure to use distal cues to get oriented in space and that impaired parietal-hippocampal network level plasticity during sleep may underlie this spatial disorientation. However, the relationship between tau and amyloid beta aggregation in this brain network and impaired spatial orientation has not been assessed. Therefore, we used several approaches, including canonical correlation analysis and independent components analysis tools, to examine the relationship between pathology profile across the parietal-hippocampal brain network and spatial reorientation learning and memory performance. We found that consistent with the exclusive impairment in 3xTg-AD 6-month female mice, only 6-month female mice had an ICA identified pattern of tau pathology across the parietal-hippocampal network that were positively correlated with behavior. Specifically, a higher density of pTau positive cells predicted worse spatial learning and memory. Surprisingly, despite a lack of impairment relative to controls, 3-month female, as well as 6- and 12- month male mice all had patterns of tau pathology across the parietal-hippocampal brain network that are predictive of spatial learning and memory performance. However, the direction of the effect was opposite, a negative correlation, meaning that a higher density of pTau positive cells predicted better performance. Finally, there were not significant group or region differences in M78 density at any of the ages examined and ICA analyses were not able to identify any patterns of 6E10 staining across brain regions that were significant predictors of behavioral performance. Thus, the pattern of pTau staining across the parietal-hippocampal network is a strong predictor of spatial learning and memory performance, even for mice with low levels of tau accumulation and intact spatial re-orientation learning and memory. This suggests that AD may cause spatial disorientation as a result of early tau accumulation in the parietal-hippocampal network.
